Conditions: Nonalcoholic Steatohepatitis (NASH) With Fibrosis
Keywords: Elafibranor NASH Nonalcoholic steatohepatitis Fatty liver disease Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2157
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the effect of Elafibranor treatment compared to placebo on 1) histological improvement and 2) all-cause mortality and liver-related outcomes in patients with nonalcoholic steatohepatitis (NASH) and fibrosis.

Detailed description:

Arms:
arm 1: Coated tablets dosed at 120mg Elafibranor; oral administration; one tablet per day before breakfast with a glass of water arm 2: Coated placebo tablets; oral administration; one tablet per day before breakfast with a glass of water

Interventions: intervention 1: Elafibranor intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
SAP_002.pdf: 
Document Type:  
Final Statistical Analysis Plans 
Document Dates:  
Statistical Analysis Plan (Surrogate Endpoint Analysis) Version 4.0 – 
 
 
 
22 April 2020 
 
 
 
Statistical Analysis Plan (Long-Term Endpoint Analysis [Final  
 
 
 
Analysis]) Version 5.0 – 23 November 2020 
Study Title:   
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 
 
 
 
III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients 
 
 
 
with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Protocol Reference Number: GFT505-315-1 
NCT Number:  
NCT02704403 
 
 
 
 








Statistical Analysis Plan (Surrogate Endpoint Analysis) 
Version: Final 
Date of Issue: 22-APR-2020 
GENFIT Protocol No. GFT505-315-1 
Study ID: RESOLVE-IT/8325398 
 
 CONFIDENTIAL 
Page 4 of 85 
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Statistical Analysis Plan (Surrogate Endpoint Analysis) 
Version: Final 
Date of Issue: 22-APR-2020 
GENFIT Protocol No. GFT505-315-1 
 Study ID: RESOLVE-IT/8325398 
 
 CONFIDENTIAL 
Page 5 of 85 
ST-AD-008 version 03 
VERSION HISTORY 
Version 
Number 
Version 
Date 
Summary and rational of change(s) 
2.0 
26 Jan 
2017 
Update with protocol amendment 1 
New section added with rules for dealing with missing or incomplete dates 
3.0 
23 Jan 
2020 
SAP split into two versions; for the SEA and long-term (final) analysis 
 
Clarifications on the SEA timing  
Additional detail and clarifications provided for analysis set definitions (FITT 
set, ITT set, ITTF1 set, PPS, FSS, Safety and SSF1) 
Addition of a new analysis set: Evaluable Efficacy Set 
 
Additional section regarding estimand definitions 
Upgrade of metabolic parameters as Key Secondary Endpoints and set up of a 
Gatekeeping procedure to control the overall type 1 error rate at 2-sided 0.01 
level. 
Addition of new secondary endpoints 
 
Clarifications of time points, visit windows and handling of missing data 
 
Update of the statistical method for the primary and sensitivity analyses of the 
primary endpoint and for the analysis of the binary secondary endpoints defined 
according to histological parameters. These analyses will be performed using 
the approach described in Ge et al. (2011) 
Clarifications on the implementation of the supplementary analysis on the 
primary endpoint using pattern mixture model  
Addition of sensitivity analysis on the primary endpoint using CMH test 
Method of pooling centers clarified (sensitivity analysis including center as 
fixed effect). 
 
Addition of descriptive statistics on demographics and baseline characteristics 
for the FSS, Safety and SSF1 populations. 
 
Addition of descriptive statistics on completion status, baseline characteristics, 
treatment exposure and treatment emergent adverse events for the subset of 
patients from the ITT set with missing biopsy results at Week 72 
Additional compliance summary up to week 72 for SEA  
 


Statistical Analysis Plan (Surrogate Endpoint Analysis) 
Version: Final 
Date of Issue: 22-APR-2020 
GENFIT Protocol No. GFT505-315-1 
 Study ID: RESOLVE-IT/8325398 
 
 CONFIDENTIAL 
Page 6 of 85 
ST-AD-008 version 03 
Addition of shift tables from baseline to week 72 and follow-up for fibrosis 
stage, ballooning, inflammation, steatosis, NAS disease activity score and SAF 
activity score 
Additional information provided regarding summaries of morphometry data 
Analyses of change from baseline in NAS disease activity score and 
Framingham risk scores aligned to have consistent assumptions of variable 
distribution at SEA and final 
Analysis of hsCRP and NT-ProBNP updated to be performed on log 
transformed values 
 
Addition of 2 subgroup analyses for primary and key secondary endpoints 
Addition of exploratory analyses for the ITTF1 population  
Addition of exploratory analyses for the FITT population  
Addition of safety analyses for SSF1 population 
 
Added raw counts of number of events for summaries of AE data 
Added clarification regarding which laboratory parameters will be analyzed 
using repeated measures ANCOVA 
Added definition and analysis of eGFR 
New figures for laboratory parameters 
 
Updated section 8. “Changes in planned analyses” according to the protocol 
amendments 
Editorial changes 
 
 
4.0 
22 Apr 
2020 
Due to changes in the definition of the long-term primary endpoint, several 
former components of the endpoint are to be considered as AEs and included in 
safety analyses 
Added definition and analysis of AESIs 
New figure for albuminuria 
Added clarifications regarding the strategy for eDISH plots 
Added clarifications regarding the categorization of subjects with serum 
creatinine increases 
Added analysis of eGFR decreases 
Removed the criteria for DILI adjudication that were not consistent with the 
protocol. 


Statistical Analysis Plan (Surrogate Endpoint Analysis) 
Version: Final 
Date of Issue: 22-APR-2020 
GENFIT Protocol No. GFT505-315-1 
 Study ID: RESOLVE-IT/8325398 
 
 CONFIDENTIAL 
Page 7 of 85 
ST-AD-008 version 03 
TABLE OF CONTENTS 
 
APPROVALS ............................................................................................................................................... 2 
REVIEWERS ............................................................................................................................................... 3 
VERSION HISTORY .................................................................................................................................. 5 
GLOSSARY OF ABBREVIATIONS ....................................................................................................... 10 
STATISTICAL ANALYSIS PLAN AMENDMENT 1 ........................................................................... 12 
1 SOURCE DOCUMENTS .................................................................................................................... 13 
2 PROTOCOL DETAILS ...................................................................................................................... 13 
2.1 Study Objectives .......................................................................................................................... 13 
2.1.1 Primary objective .............................................................................................................. 13 
2.1.2 Secondary objectives ......................................................................................................... 13 
2.1.3 Exploratory objectives ...................................................................................................... 15 
2.2 Overall Study Design .................................................................................................................. 15 
2.3 Sample Size and Power (Surrogate Endpoint Analysis) .......................................................... 16 
2.3.1 Resolution of NASH ......................................................................................................... 16 
2.4 Estimand strategy ....................................................................................................................... 16 
2.4.1 Primary estimand .............................................................................................................. 16 
2.4.2 Key secondary estimands .................................................................................................. 17 
3 EFFICACY AND SAFETY VARIABLES ........................................................................................ 17 
3.1 Primary Efficacy Endpoint ........................................................................................................ 17 
Surrogate endpoint - resolution of NASH .................................................................................... 17 
3.2 Secondary Efficacy Endpoints ................................................................................................... 17 
3.3 Safety Variables ........................................................................................................................... 19 
4 PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES ................................................. 19 
5 ANALYSIS POPULATIONS .............................................................................................................. 19 
5.1 Enrolled Set ................................................................................................................................. 19 
5.2 Safety Set ...................................................................................................................................... 19 
5.3 Intent-to-treat Set (ITT) ............................................................................................................. 20 
5.4 Evaluable Efficacy Set (EES) ..................................................................................................... 20 
5.5 Per Protocol Set (PPS) ................................................................................................................ 20 
5.5.1 Important Protocol Deviations Leading to Exclusion from the PPS Analysis ................. 20 
5.6 Other Populations ....................................................................................................................... 24 
5.6.1 Full Safety Set (FSS) ......................................................................................................... 24 
5.6.2 Full Intent-to-Treat Set (FITT).......................................................................................... 24 


Statistical Analysis Plan (Surrogate Endpoint Analysis) 
Version: Final 
Date of Issue: 22-APR-2020 
GENFIT Protocol No. GFT505-315-1 
 Study ID: RESOLVE-IT/8325398 
 
 CONFIDENTIAL 
Page 8 of 85 
ST-AD-008 version 03 
5.6.3 Intent-to-Treat F1 Cohort Set (ITTF1) .............................................................................. 24 
5.6.4 Safety F1 Cohort Set (SSF1) ............................................................................................. 24 
6 DATA HANDLING ............................................................................................................................. 24 
6.1 Time points and Visit Windows ................................................................................................. 24 
6.2 Handling of Dropouts or Missing Data ..................................................................................... 26 
6.2.1 Handling of Missing Data ................................................................................................. 26 
6.2.2 Handling of Missing or Incomplete Dates ........................................................................ 27 
7 STATISTICAL METHODS ............................................................................................................... 28 
7.1 Surrogate Endpoint Analysis ..................................................................................................... 28 
7.2 General Principles ....................................................................................................................... 28 
7.3 Patient Disposition and Data Sets Analysed ............................................................................. 29 
7.4 Protocol Deviations ..................................................................................................................... 30 
7.5 Demographics and Other Baseline Characteristics ................................................................. 30 
7.5.1 Medical History ................................................................................................................. 31 
7.5.2 Prior and Concomitant Medications.................................................................................. 31 
7.5.3 Substance Use History ...................................................................................................... 32 
7.5.4 Safety, Diet and Lifestyle Factors ..................................................................................... 32 
7.6 Measurements of Treatment Compliance ................................................................................. 32 
7.7 Efficacy ......................................................................................................................................... 33 
7.7.1 Primary Efficacy Analysis ................................................................................................ 35 
7.7.2 Secondary Efficacy Analysis ............................................................................................ 37 
7.7.3 Supplementary and Sensitivity Analysis ........................................................................... 54 
7.7.4 Subgroup Analysis ............................................................................................................ 58 
7.7.5 Exploratory Analysis ......................................................................................................... 61 
7.8 Safety ............................................................................................................................................ 63 
7.8.1 Extent of Exposure ............................................................................................................ 64 
7.8.2 Adverse Events.................................................................................................................. 64 
7.8.3 Laboratory Evaluations ..................................................................................................... 68 
7.8.4 Vital Signs ......................................................................................................................... 71 
7.8.5 Electrocardiograms ........................................................................................................... 72 
7.8.6 Physical Examination ........................................................................................................ 72 
7.8.7 Other Safety Variables ...................................................................................................... 72 
7.9 Interim Analysis .......................................................................................................................... 73 
8 CHANGES IN PLANNED ANALYSES ............................................................................................ 73 
9 DATA ISSUES ...................................................................................................................................... 73 
10 REFERENCES ..................................................................................................................................... 73 
11 APPENDICES ...................................................................................................................................... 75 


Statistical Analysis Plan (Surrogate Endpoint Analysis) 
Version: Final 
Date of Issue: 22-APR-2020 
GENFIT Protocol No. GFT505-315-1 
Study ID: RESOLVE-IT/8325398 
 
 CONFIDENTIAL 
Page 9 of 85 
ST-AD-008 version 03 
APPENDIX I - SCHEDULE OF EVENTS .............................................................................................. 75 
APPENDIX II - TABLE, FIGURE AND LISTING SHELLS ............................................................... 84 
APPENDIX III – SF-36 QUALITY OF LIFE SCORING MANUAL .................................................. 85 
 

























































































































































































































































Prot_001.pdf: 
Document Type:  
Document Dates: 
Study Title: 
Final Protocol(s) 
Protocol Version 1 – 15 January 2016 
Protocol Version 2 – 06 January 2017 
Protocol Version 3 – 03 April 2017 
Protocol Version 4 – 03 January 2020 
Protocol Version 5 – 20 April 2020 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 
III Study to Evaluate the Efficacy and Safety of Elafibranor in 
Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Protocol Reference Number: GFT505-315-1 
NCT Number:  
NCT02704403 






Clinical Trial ELAFIBRANOR-315-1  
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GENFIT 
CONFIDENTIAL 
Page 3 of 129 
CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1.0 
DATE: 
January 15, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Trial ELAFIBRANOR-315-1  
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IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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Page 6 of 129 
CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality,  progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Exploratory objectives 
 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 


Clinical Trial ELAFIBRANOR-315-1  
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o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
 
Safety secondary objectives 
 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
 
NAS ≥4. 
 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine aminotransferase 
(ALT), obesity defined by a body mass index (BMI) 30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
 
674 patients in placebo group  
 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
 
Screening Period: Week-12 to Week -1 prior to randomization. 
 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Body Mass Index ≤45 kg/m². 


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4. Females participating in the study must either not be of childbearing potential (hysterectomy, 
bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation 
of menses for at least 12 months due to ovarian failure) or using efficient double contraception: 
hormonal contraception (including patch, contraceptive ring, etc), intra-uterine device, or other 
mechanical contraception method + condom or diaphragm or spermicide for the full duration of the 
study and for 1 month after the end of treatment. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic 
acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in anti-diabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e. implementation of a new anti-diabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfamides, or insulin. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol Consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus RNA) 


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o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
25. Positive anti-human immunodeficiency virus antibody. 
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. International normalized ratio >1.4. 
29. platelet count <100,000/mm3. 
30. Serum creatinine levels >135 µmol/L (>1.53 mg/dL ) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 
repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 


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Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
 
liver transplantation 
 
MELD score ≥15 
 
HCC 
 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints  
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 


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Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
 
Regulatory/ethics committee submission: January 2016 
 
Initiation visits: February 2016 – March 2017 
 
Recruitment period: February 2016 – December 2017 
 
FPFV: February 2016 
 
Interim analysis : August – October 2018 
 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction and stroke events as 
defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 








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8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
10. ECG will be performed every 48 weeks starting at V9. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 






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= fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; 
NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing protein 3; PT  = 
prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = triglyceride; VLDL-C 
= very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:  
 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 3 
STUDY CONTACTS ................................................................................................................................ 4 
CLINICAL TRIAL SYNOPSIS ................................................................................................................... 6 
TABLE OF CONTENTS ......................................................................................................................... 21 
TABLE OF TABLES .............................................................................................................................. 26 
TABLE OF FIGURES ............................................................................................................................ 26 
LIST OF ABBREVIATIONS .................................................................................................................... 27 
1. 
INTRODUCTION ................................................................................................................... 30 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 30 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 30 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 32 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 33 
1.4.1. 
Pharmacology ........................................................................................................... 33 
1.4.2. 
Safety pharmacology ................................................................................................. 34 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 34 
1.4.4. 
Toxicology ................................................................................................................ 35 
1.5. 
CLINICAL STUDIES ............................................................................................................... 36 
1.5.1. 
Phase I program ........................................................................................................ 36 
1.5.2. 
Phase II program ...................................................................................................... 37 
1.6. 
CONCLUSION ....................................................................................................................... 40 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 40 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 41 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 41 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 41 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 42 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 42 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 43 
2. 
TRIAL OBJECTIVES ............................................................................................................... 45 
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 45 
2.1.1. 
Surrogate endpoint -Interim analysis .......................................................................... 45 
2.1.2. 
Long-term endpoint ................................................................................................... 45 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ............................................................... 45 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 46 
2.4. 
EXPLORATORY OBJECTIVES.................................................................................................. 46 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .......................................................................... 47 


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2.6. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 47 
3. 
TRIAL DESIGN ..................................................................................................................... 49 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 49 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 49 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 50 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 50 
3.5. 
STUDY PERIODS .................................................................................................................. 50 
3.6. 
SCREENING PERIOD ............................................................................................................. 50 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .............. 50 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 52 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 52 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 52 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 53 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 53 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 54 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 54 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ................................................ 55 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 55 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 56 
3.11. OPTIONAL VISITS ................................................................................................................ 58 
3.11.1. 
Retesting screening visits ........................................................................................... 58 
3.11.2. 
Unscheduled visits ..................................................................................................... 58 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 58 
4. 
PATIENT SELECTION ............................................................................................................ 59 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 59 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 60 
5. 
TRIAL PROCEDURES ............................................................................................................. 63 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 63 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 63 
5.1.2. 
Dietary and fluid restrictions ....................................................................................... 63 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 64 
5.2.1. 
Handling of patient withdrawal ................................................................................... 64 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 64 
5.2.3. 
Patient discontinuation from the Study ........................................................................ 65 
5.2.4. 
Patients lost to follow-Up ........................................................................................... 66 
5.2.5. 
Replacement ............................................................................................................. 66 
5.2.6. 
Premature discontinuation of the study ....................................................................... 66 
6. 
ASSESSMENTS ..................................................................................................................... 67 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 67 


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6.1.1. 
Histological assessments ............................................................................................ 67 
6.1.2. 
Biological assessments ............................................................................................... 68 
6.1.3. 
Constitution of biobank .............................................................................................. 69 
6.1.4. 
Pharmacokinetics evaluation ...................................................................................... 69 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 70 
6.2.1. 
Physical examination.................................................................................................. 70 
6.2.2. 
Vital signs ................................................................................................................. 70 
6.2.3. 
Electrocardiogram...................................................................................................... 71 
6.2.4. 
FibroScan .................................................................................................................. 71 
6.2.5. 
Quality of life questionnaire ........................................................................................ 72 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 72 
6.3.1. 
Creatine phosphokinase ............................................................................................. 72 
6.3.2. 
Liver function monitoring ........................................................................................... 72 
6.3.3. 
Threshold for diagnostic of cirrhosis ............................................................................ 74 
6.4. 
SAFETY DATA REVIEW ......................................................................................................... 74 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 74 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 75 
7. 
TREATMENTS ....................................................................................................................... 78 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 78 
7.2. 
PACKAGING AND LABELING .................................................................................................. 78 
7.2.1. 
Packaging ................................................................................................................. 78 
7.2.2. 
Labeling .................................................................................................................... 78 
7.2.3. 
Dosage and administration of Elafibranor and placebo ................................................. 79 
7.2.4. 
Prior and concomitant medications ............................................................................. 79 
7.3. 
STORAGE CONDITIONS ........................................................................................................ 79 
7.4. 
DISPENSING OF TREATMENT ................................................................................................ 79 
7.5. 
TREATMENT REPLACEMENT .................................................................................................. 80 
7.6. 
PROCEDURE FOR BLINDING ................................................................................................. 80 
7.7. 
PROCEDURE FOR UNBLINDING ............................................................................................. 80 
7.8. 
STUDY DRUG COMPLIANCE .................................................................................................. 81 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 81 
7.10. OTHER MEDICATION ............................................................................................................ 81 
7.10.1. 
Handling of concomitant medication ........................................................................... 81 
7.10.2. 
Non-permitted medication .......................................................................................... 82 
7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) ............................................................................................................... 82 
7.10.4. 
Permitted medication ................................................................................................. 83 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 84 


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8.1. 
DEFINITIONS ....................................................................................................................... 84 
8.1.1. 
Adverse event ........................................................................................................... 84 
8.1.2. 
Serious adverse events .............................................................................................. 85 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 86 
8.1.4. 
Adverse drug reaction ................................................................................................ 87 
8.1.5. 
Unexpected adverse event ......................................................................................... 87 
8.2. 
ASSESSMENTS ..................................................................................................................... 87 
8.2.1. 
Intensity assessment ................................................................................................. 87 
8.2.2. 
Relation to the study treatment .................................................................................. 88 
8.2.3. 
Action taken and outcome .......................................................................................... 88 
8.3. 
REPORTING ......................................................................................................................... 89 
8.3.1. 
Reporting an adverse event ....................................................................................... 89 
8.3.2. 
Reporting a serious adverse event .............................................................................. 89 
8.3.3. 
Follow-up .................................................................................................................. 91 
8.4. 
POST STUDY REPORTING REQUIREMENTS ............................................................................ 91 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ................................................................................ 91 
8.6. 
SPECIAL SITUATION REPORTS ............................................................................................. 92 
8.6.1. 
Pregnancy ................................................................................................................. 92 
8.6.2. 
Medication error ........................................................................................................ 92 
8.6.3. 
Misuse ...................................................................................................................... 92 
8.6.4. 
Overdose .................................................................................................................. 93 
8.6.5. 
Abuse ....................................................................................................................... 93 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ....................................................................... 94 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ................................................................. 94 
9.2. 
ENDPOINTS ......................................................................................................................... 94 
9.2.1. 
Surrogate endpoint - resolution of NASH ..................................................................... 94 
9.2.2. 
Long-term endpoint – time to clinical event/death ....................................................... 94 
9.2.3. 
Key Secondary Endpoint ............................................................................................ 95 
9.2.4. 
Other Secondary Endpoints ........................................................................................ 95 
9.2.5. 
Exploratory endpoints ................................................................................................ 96 
9.3. 
ANALYSIS SETS .................................................................................................................... 96 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS...................................................................................... 97 
9.4.1. 
Resolution of NASH.................................................................................................... 97 
9.4.2. 
Long-term endpoints ................................................................................................. 97 
9.5. 
OTHER STATISTICAL ANALYSIS ............................................................................................ 98 
9.5.1. 
Key secondary endpoint ............................................................................................. 98 
9.5.2. 
Other secondary endpoints ........................................................................................ 98 
9.5.3. 
Subgroup analyses .................................................................................................... 99 


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9.5.4. 
Exploratory analyses .................................................................................................. 99 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ............................................................................. 99 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 100 
9.7.1. 
Resolution of NASH.................................................................................................. 100 
9.7.2. 
Time to clinical event/death ..................................................................................... 100 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 101 
9.8.1. 
Interim analysis ....................................................................................................... 101 
9.9. 
BLINDED REASSESSMENT ................................................................................................... 102 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 103 
10.1. CRF AND SOURCE DOCUMENTS .......................................................................................... 103 
10.2. RETENTION OF RECORDS ................................................................................................... 103 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 105 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 105 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 106 
11.3. QUALITY ASSURANCE ......................................................................................................... 106 
12. 
ETHICS AND REGULATORY ................................................................................................. 107 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 107 
12.2. COMPETENT AUTHORITY ................................................................................................... 108 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 108 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 108 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 109 
13. 
FINANCING AND INSURANCE .............................................................................................. 110 
13.1. FINANCIAL ISSUES ............................................................................................................. 110 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 110 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 111 
14.1. STUDY REPORT .................................................................................................................. 111 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 111 
15. 
REFERENCES LIST .............................................................................................................. 113 
APPENDICES .................................................................................................................................... 116 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 116 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 125 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 126 
APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 128 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 129 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 13 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 17 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 72 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 76 
 
 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
20 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 


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HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNF 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 


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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)/ modulators with preferential activity on PPAR over 
PPAR (about fivefold more potent on human PPAR [hPPAR] than on hPPAR). The PPAR properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPAR 
response) and human hepatocytes (a mixed PPAR/ response). 
The PPAR receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPAR activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPAR compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPAR appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPAR agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPAR ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNF, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPAR knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNF, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPAR knockouts. 
Finally, in a short clinical trial, a pure PPAR agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing GT.16 


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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPAR 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPAR encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPAR and PPAR in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPAR-dependent and PPAR-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPAR reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPAR -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPAR 


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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPAR reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 


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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPAR-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPAR-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 


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1.4.4.4. 
Photoxicity studies 
The phototoxic potential of elafibranor  has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of photoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 


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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 


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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 


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(-20% to -35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. . Serious adverse events (SAE) were reported 
in 27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor  120 mg/d). Of 


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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor  120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 


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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 


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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatine 
ration, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 


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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 


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 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
 
SAE, AE, physical examination, vital signs, medical history, ECG 
 
hematological parameters 
 
liver function parameters 
 
renal function parameters (including urinalysis) 


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 
cardiac function parameters 
 
metabolic parameters 
 
other biochemical safety markers. 
 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
 
Elafibranor 120 mg 
 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 


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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
 
Signature of informed consent witnessed by the Investigator or designated person. 
 
Patient number allocation via IXRS. 
 
Check medical history/demographics. 
 
Check inclusion/exclusion criteria (described in Section 4). 
 
Physical examination (described in Section 6.2.1). 


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 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
 
Record vital signs (described in Section 6.2.2). 
 
Record height, weight, and waist circumference. 
 
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10 
and APPENDIX III: Permitted/Non-permitted medication) 
 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1. 
 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1. 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
 
Blood samples (described in Table 2). 
 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
 
Urinalysis dipstick. 
 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 31, 
and 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 2 digits corresponding to the site number (this number will be predefined), 
 Last 2 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
 
Check inclusion/exclusion criteria (detailed in Section 4). 
 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 


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 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference (V1, V3, V5, and V7, only). 
 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 


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The following procedures will be performed at each visit from V8 to Vn: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
 
FibroScan (described in Section 6.2.4) 
 
Drug accountability 
 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety and IP compliance control. If any information during this phone contact requires a visit, 
the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS 
registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 


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All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, and Figure 1. 
The following procedures will be performed at the EOT Visit: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (described in Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (described in Section 6.2.3) 
 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 


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including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
 
IXRS registration. 
 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
 
Reporting of any change in diet and life style factors 
 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 


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3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization.  
 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral 
oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses 
for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal 
contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical 
contraception method + condom or diaphragm or spermicide for the full duration of the study and for 
1 month after the end of treatment. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 
treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or 
ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy.  
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions:  
 
No change in dose for patients treated by GLP-1 agonists 


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 
No qualitative change (i.e. implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfamides, or insulin. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients.  
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
 
Positive hepatitis B surface antigen (HBsAg) 
 
HCV RNA 
 
Suspicion of drug-induced liver disease 
 
Alcoholic liver disease 
 
Autoimmune hepatitis 


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 
Wilson’s disease hemochromatosis 
 
Primary biliary cirrhosis, primary sclerosing cholangitis 
 
Genetic hemochromatosis 
 
Known or suspected HCC 
 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
25. Positive anti-human immunodeficiency virus (HIV) antibody. 


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26. AST and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. INR >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, and 
Figure 1) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 


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 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 


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 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
 
Non-compliance with the study treatment 
 
Uncooperative patient 
 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 


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5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
 
Needle core biopsy 
 
Biopsy obtained with a 16 or lower gage needle 
 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 


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The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
 
HIV ab I/II 
 
HBsAg 
 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
 
To discover or validate biomarkers in NASH and related diseases. 
 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 


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Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 


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6.2.2.1. 
Important points for clinical blood pressure measurement: 
 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 


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Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e. ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 
must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 


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For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 


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 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visitin the Long-
term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or a any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or 
ascites, then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will 
have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction and stroke events 
as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, 
and unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 


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6.6. 
GUIDANCE FOR INVESTIGATORS 
The safety and tolerability of GFT505 were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication.  
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 


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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 


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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI.  
Based on the findings of non-clinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, GFT505 may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014).  
As such, all clinical trials with GFT505 including women of childbearing potential request a negative 
pregnancy test before randomization, with effective contraceptive measures throughout the sudy. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between GFT505 and contraceptive steroids, the exclusive use of hormonal contraceptive methods during 
clinical trials should be avoided, and they should be accompanied by barrier methods.    
Conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with GFT505. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in phase 2 trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
GFT505 treatment, up to 1 month after end of study treatment. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 


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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed) , and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 


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value defined in the supply strategy. Following randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 


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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
 
Blister identification 
 
Quantity destroyed 
 
Method of destruction 
 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 


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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
 
Glitazones (pioglitazone & rosiglitazone) 
 
Fibrates 
 
Corticosteroids (parenteral & oral chronic administration only) 
 
Amiodarone 
 
Tamoxifen 
 
Methotrexate 
 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 


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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfamides 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfamides and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
 
Test result is associated with accompanying symptoms 
 
Test result requires additional diagnostic testing or medical/surgical intervention 
 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
 
Overdose without clinical sequelae 


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 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
 
Uncomplicated pregnancy 
 
An induced elective abortion to terminate a pregnancy without medical reason 
 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (see Section 8.1.2.1) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g. wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 


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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 
Hospitalization for survey visits or annual physicals fall in the same category. 
 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias or convulsions that do not result in hospitalization 
 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
 
As an outcome event, progression to cirrhosis should not be included as AE. 
 
Death is an outcome of an AE, not an AE in itself. 


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 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 


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 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
 
Dose not changed – in case no action is taken regarding the study drug 


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 
Unknown 
 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
 
Recovered/resolved 
 
Recovering/resolving 
 
Not recovered/not resolved 
 
Recovered/resolved with sequelae 
 
Fatal 
 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening visit and ends at the 
last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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 
SAEs (including events related to study procedures) 
 
SADRs 
 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 


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 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 


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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 


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 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. . Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
 
Full Intent-To-Treat Set (FITT): all randomized patients.  
 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS,and exploratory F1 cohorts (study population and efficacy data) will analyzed 
based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 


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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 


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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
Presence of type 2 diabetes (yes, no) 
 
Gender (male, female) 
 
Fibrosis (F2, F3) 
 
Geographic region (North America, Europe, South America, Rest of World) 
 
Race (Caucasian, Hispanic, Other) 
 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided =0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided =0.01 for resolution of NASH and two-sided =0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided =0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided =0.01 for resolution of NASH and 
two-sided =0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided =0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
 
=0.01 two-sided 
 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
 
Pooled variance 
 
Randomization ratio of 2:1 (elafibranor: placebo) 
 
8% response in the control group 
 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
 
72 month maximum follow-up 
 
=0.04 two-sided 
 
Annual event rate of 7% for the placebo group 
 
Hazard ratio of 0.75 in favor of the elafibranor group 
 
4% annual drop-out rate over 72 months 
 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 


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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. . 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e. 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 


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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 


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The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santiban˜ez C, Haim D, et al. Enhancement in liver nuclear factor-kb (nf-kb) and 
activator protein 1 (ap-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-
acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. Epub 
2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. 
Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al.,Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, 
and 
increases 
fatty 
acid 
oxidation 
in 
moderately 
obese 
men. 
Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell. Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell. Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 


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Appendices 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


 
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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
2.0 
DATE: 
January 06, 2017 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
  
 
 
 
group.com 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
ePRO 
 
 
 
 
 
 
 
 


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AMENDMENT 1: 06 JANUARY 2017 
Amendment 1 addresses inconsistencies in the original protocol and increases clarity. It also details the statistical analyses to be consistent with the Statistical Analysis 
Plan. Revisions were made to protocol sections noted below as well as to the study synopsis, the study general assessment schedule (Table 1), study biological 
assessment schedule (Table 2), study duration and visit schedule (Figure 1), and throughout the protocol text as required. Added text is bolded; deleted text is struck 
through. 
Summary of major changes to the protocol: 
Section 
New Text 
Table 2: 
STUDY BIOLOGICAL 
ASSESSMENT SCHEDULE 
(amendments not 
described anywhere else in 
protocol) 
Screening Visit 1 - chemistry panel 
HbA1c32, fasting plasma glucose, Insulin (fasting), HOMA –IR, creatinine, eGFR3, GGT, AST, ALT, CPK32, alkaline phosphatase, total and conjugated bilirubin, sodium, and 
TG, and MELD score 
V1 to Vn total chemistry panel 
HbA1c, fasting plasma glucose, creatinine, eGFR, GGT, AST, ALT, CPK, alkaline phosphatase, total proteins, albumin, electrolytes (sodium, potassium, chloride, calcium), uric 
acid, urea (BUN), total and conjugated bilirubin, hsCRP, total cholesterol, nonHDL-C, HDL-C, TG, calculated VLDL-C, ApoAI, ApoB, and calculated LDL-C, and MELD score 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma  while plasma and serum samples are to be taken 
should be retrieved at every visit ONLY for patients who have signed the pharmacogenomics genetic and biomarker ICF. 


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Section 
New Text 
Figure 2:  
PREGNANCY TESTING 
SCHEDULE FOR WOMEN 
OF CHILDBEARING 
POTENTIAL 
New figure included for pregnancy testing schedule for women of childbearing potential. Appropriate text added throughout protocol as 
required. 
 
Section 1.9.2  
Primary endpoint for 
clinical outcome 
(postapproval 
confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of elafibranor on the progression 
to cirrhosis, all-cause mortality, and liver-related clinical outcomes as measured by the onset time to first occurrence of any of the listed 
adjudicated events (clinical outcomes composite endpoint). 


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Section 
New Text 
Section 1.11 
Rationale for safety 
monitoring 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the renal safety markers (plasmatic 
or urinary parameters), including but not limited to albumin-creatinine ration, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), 
N acetyl β D -glucosaminidase β-NAG, kidney injury molecule-1 (KIM 1). Serum creatinine, and modification of diet in renal disease 
(MDRD) derived estimated glomerular filtration rate (eGFR) creatinine clearance, and the results of urinalysis (dipstick) will be 
reported at each visit, as well as blood urea nitrogen. 
Section 2.1.2 
Long-term endpoint 
Note: this change was also 
implemented in Section 
3.10 and Section 9.2.2 
 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence The onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites  
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to hospitalization or 
transfusion). 
Section 3.6.1 
Screening visits SV1 
(Week -12 to Week -8) and 
SV2 (Week -12 to 
Week -4): 
 
• Signature of informed consent witnessed by the Investigator or designated person. Note: The signature of the informed consent 
may also be performed before SV1.  
• Check concomitant/prior medication (within 30 days 6 months prior to Screening) (described in Section 7.12 and APENDIX III: 
Permitted/non-permitted medication) 
• Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for central confirmation of NASH diagnosis 
(described in Section 6.1.1.2). This historical diagnostic biopsy should be obtained within 6 months prior to the planned Randomization 


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Section 
New Text 
Screening Visit (V1). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, total bilirubin, INR), at least 2 
consecutive assessments in at least 8 weeks apart between visit SV1 and V1 should be performed. Visits SV1 and V1 should be scheduled 
at least 8 weeks apart in order to have 2 consecutive baseline values of AST, ALT, total bilirubin, and INR for DILI 
adjudication (using SV1 and V1 kits).according to this requirement. 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without waiting for HCV Ab 
results. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR), or creatine phosphokinase (CPK) results or additional 
testing of hepatitis C virus (HCV) RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 13,12, 30, and 31 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they agree to participate in the study 
and sign the ICF. Each patient who will have has signed the ICF will be allocated a patient number composed of 79 digits which is 
generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 23 digits corresponding to the site number (this number will be predefined), 
 Last 23 digits corresponding to the numerical order of the patient entry at the study site. 
Section 3.7.2   
First Treatment Period 
visits V1 to V7 (Week 0 to 
Week 72) 
The following procedures will be performed at each of the 12 week visits from V1 to V7 : 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous visit (for WOCBP 
only, every visit from V1 


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Section 
New Text 
Section  3.8.1 
Long-term Treatment 
Period Visits (V8 to Vn) 
The following procedures will be performed at each visit from V8 to Vn: 
• 
Quality of life assessment (V8, V9, V11, and every 48 weekly weeks thereafter Section 6.2.6) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous visit (for WOCBP 
only, every visit from V1 
Section 3.8.2  
Long-term Treatment 
Period phone visits (PV1 to 
PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and lifestyle, concomitant 
medications, clinical outcomes, safety, home pregnancy test results, and IP compliance control. If any information during this phone 
contact requires a visit, the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be 
performed for each phone visit. 
Section 3.9  
End of Study Treatment 
Visit 
 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return (if required). The 
following procedures will be performed at the EOT Visit: 
• IXRS registration 
• Physical examination (described in Section 6.2.1) 
• Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits 
• Check concomitant/prior medication (described in Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• Quality of life assessment (described in Section 6.2.6) 
• Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• Blood samples (described in Table 2) 


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Section 
New Text 
• Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent signed) 
• Urinalysis and urinary dipstick (described in Table 2) 
• Urinary pregnancy test (for WOCBP only) 
• Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2) since previous visit (for WOCBP 
only) 
• Record waist circumference 
• 12-lead ECG (described in Section 6.2.4) 
• Drug accountability. 
3.11.1 
Retesting screening visits 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test 
and maximum 2 weeks prior to planned Randomization.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
Section 4.1 
Inclusion criteria 
3. 
BMI ≤45 kg/m2 
3. Females participating in this the study must either not be of nonchildbearing potential (hysterectomy, bilateral oophorectomy, 
medically documented ovarian failure, or >50 years of age with or using highly efficient contraception for the full duration of 
the study and for 1 month after the end of treatment, as described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure) or using efficient double contraception; hormonal,   


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Section 
New Text 
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient) 
o Using a highly effective nonhormonal method of contraception (including patch, contraceptive ring, etc bilateral tubal 
occlusion, vasectomized partner or intra-uterine device, or opther mechanical) 
o 
Double contraception method + condom or diaphragm with barrier AND highly effective hormonal method of 
contraception (oral, intravaginal or spermicide for the full duration of the study and for 1 month after the end of treatment 
transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; 
oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at least 1 month prior to 
Randomization. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, change 
in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., implementation of a new 
anti-diabetic therapy) for patients treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter 
(SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are 
allowed in the 6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ judgment, except 
for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the end of treatment. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by anti diabetic drugs, no change is allowed 


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Section 
New Text 
within 6 months prior to diagnostic liver biopsy, under the following conditions:  
• no change in dose for patients treated by GLP 1 agonists  
• no qualitative change up to Randomization (i.e., implementation of a new anti diabetic therapy) for patients treated with metformin, 
gliptins, sulfamides, or insulin. 
 .• no qualitative change up to 72 week of treatment (V7) (i.e., implementation of new drug) for patients treated with sodium/glucose 
cotransporter 2 (SGLT2) inhibitors. 
Section 4.2 
Exclusion criteria 
1. 
Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the course of the study. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening such as: acute cardiovascular 
episode, stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization 
procedures). 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to donate blood or blood products at 
any time during the trial and in the 2 months following the end of the study. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV C infection, or positive HCV Ab at Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 


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Section 
New Text 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the recommendations of National 
Law in force applicable to clinical Trials. 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, or ezetimibe, or nonfibrate lipid 
lowering drugs before Screening may participate if the dosage has been kept constant for at least 2 months prior to Screening. 
26. Total Conjugated bilirubin >25 µmol/L (1.50 mg/dL) due to altered hepatic function. NOTE: Gilbert Disease patients are 
allowed into the study. 
27. INR >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 
Section 5.1.3  
Home pregnancy test 
for women of 
childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy test kits will be 
supplied at each visit to WOCBP and these are to be performed as per the kit instructions every 4 weeks between study 
visits. Negative results are to be reported at the next scheduled visit or telephone visit (see Table 1 and Figure 2). In the 
event of a positive result the patient must discontinue study drug immediately and report the result to the Investigator as 
soon as possible (see Section 8.6.1). 
Section 5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without protection from 
V1 through to the end of the study (see Section 1.4.4.4). 
5.3. 
Patient rescreening 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which allows him/her 
to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening the patient will need to sign a 
new informed consent, will be entered as a new patient, with a new patient number. 


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Section 
New Text 
6.1.2.2 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during the study on WOCBP. These 
tests will also be given to the WOCBP to perform a pregnancy test at home every 4 weeks in between visits (see Section 
5.1.3).  
6.1.4 Pharmacokinetic 
evaluation 
Section removed and all text throughout relating to pharmacokinetic assessments/analysis removed. This will be addressed through a 
specific sub-study protocol. 
Section 9  
Statistical methods and 
data analysis 
In all circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first approved version of the SAP 
should be available within 3 months of protocol submission first patient randomized and before the first DSMB meeting. 
9.4.1 
Resolution of NASH 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of the 72 week treatment period 
will be summarized by treatment group. The main analysis will be performed using a logistic regression model, with fixed terms for 
treatment, type 2 diabetes (yes, no), gender (male, female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to 
calculate the odds ratio (elafibranor/placebo) and 99% 95% confidence interval. The main confirmatory analysis will be performed when 
approximately 50% of patients (at least 1023) F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
9.4.2 
Long-term endpoints 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage, 
and baseline NAS. The Cox proportional hazards model will be used to calculate the hazard ratio (elafibranor/placebo) and 96% 95% 
confidence interval. This will be performed when at least 456 patients experience a clinical event/death. The time to clinical 
event/death and time to first cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s 
model, log rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36  


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Section 
New Text 
Section 9.5.3  
Subgroup analyses 
• Race (Caucasian, hispanic, Other) 
• Ethnicity (Hispanic, not Hispanic) 
• Age (<5560, ≥5560 years). 
Section 9.6.  
Strategies to control type I 
error 
The overall type I error for this study is two sided α=0.05. The alpha for the primary endpoints will be split 20%/80%, with two sided 
α=0.01 for resolution of NASH and two sided α=0.04 for time to clinical event/death. The overall type I error for the primary endpoints in 
this study is two-sided α=0.05. The alpha for the primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH 
and two-sided α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. If the resolution of NASH without 
worsening of fibrosis endpoint is statistically significant, the key secondary endpoint, improvement of fibrosis according to NASH CRN 
scoring, will be tested in a confirmatory manner with a two-sided α=0.501. 
Section 9.9.  
Blinded reassessment 
Interim analysis 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or discontinued from the 72 week 
treatment period. The number of patients enrolled may be increased at this time and/or total duration extended. No adjustment will be 
made to the targeted number of events required for the final analysis of the long term endpoint, so no adjustment for control of type I 
error should be required for this reassessment. An adaptive design interim analysis will be performed after 140 primary events 
(approx. 30% of the 456 required events) have been accrued. The interim analysis will be performed by an unblinded team 
separate from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and provide 
final recommendations regarding trial termination due to futility and adjustment of the target number of primary events. 
Details will be in the DSMB Charter and SAP. 




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Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 
• 
the version number and date were updated throughout the protocol 
• 
typographical errors and formatting were corrected throughout the protocol 
• 
abbreviation was added to the list of abbreviations for FITT 
• 
amendment of study duration dates 
• 
amendment of study contact details: amendment of study drug supplier contact information: 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
Monitor 
 
 
 
 
 
 
 
 
 
Project 
Director 
 
  
 
 
 
 
Senior Project 
Manager 
 
 
 
IXRS  
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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• 
Section 4.2. Exclusion Criteria 
Minor changes to exclusion criteria 1, 5, 6, 12, 20, 26, and 30 to clarify requirements 
• 
Section 5.1.1 Standard Diet and exercise recommendations 
Text deleted to remove specific wording for compliance question 
• 
Section 6.1.1.1. Recommendations related to liver biopsy 
Note: Liver biopsy should be performed according to the good practices and local hospital 
standards, including the required exams prior to or on the day of the biopsy; Thus, the 
recommendations were simplified as below, to allow sites to follow their local requirements. 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the 
biopsy, and the risks to the patient should not outweigh the potential benefits. This will be 
assessed by the Investigator according to local practice. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of 
imaging of the liver within the preceding weeks. This will allow the detection of abnormal anatomy 
in the area of the proposed biopsy. 
 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding 
adequate reading, other available slides or new slides to be prepared from an available 
block of tissue may be requested to the site. 
• 
Section 6.1.2. Biological assessments 
Text amended for increased clarity of procedural requirements 
• 
Section 6.1.2.3 Serology (SB1) 
Text amended for increased clarity of procedural requirements 
• 
Section 6.2.1. Physical examination 
Text amended for increased clarity of procedural requirements. 
• 
Section 6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest 
and the lowest rib in cm during expiration. The measuring tape should be snug but not 
compressing the skin and held parallel to the floor. The measurement is to be made at 
normal respiration. 
• 
Section 6.2.5 FibroScan 
Text updated for increased clarity of procedural requirements 
• 
Section 6.3.1 Creatine phosphokinase 
Text amended for increased clarity of procedural requirements  


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• 
Section 6.3.2 Liver function monitoring 
In all cases, whether baseline AT values are normal or elevated, an increase of 
AT>10 x ULN will lead to permanent discontinuation of the patient from study drug, 
and scheduling of EOT visit (Section 3.9). 
• 
Section 6.3.2.1 Monitoring of patients with normal baseline aminotransferase values 
Text amended for increased clarity of monitoring requirements 
• 
Section 6.3.2.2 Monitoring of patients with increased baseline aminotransferase AT values 
Text amended for increased clarity of monitoring requirements 
• 
Section 6.3.2.3 Monitoring of all patients 
Section deleted, text amended and moved to Section 6.3.2.1 
• 
Section 6.3.3. Threshold for diagnosisic diagnosis of cirrhosis 
Text amended for increased clarity of procedural requirements 
• 
Section 6.4. Safety & efficacy data review 
An independent DSMB will be established in order to review the progress of the study and to 
perform a safety data review on a regular basis during the trial to protect patient welfare and 
preserve study integrity. The DSMB will also review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and 
adjustment of the target number of primary events. A detailed description of the 
interim analysis procedures and decision-making process will be provided in the DSMB 
Charter. 
The DSMB will consist of at least 54 experienced physicians (1 each of endocrinologist, 
1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom 
will be independent of the participants in the study. TheA DSMB Charter will define the role, 
responsibilities, rules, and tasks of the DSMB. 
• 
Section 6.5. Clinical event committee 
The CEC will specifically assess and adjudicate conduct adjudication of all disease progression 
events included in the primary composite efficacy long-term endpoint (Section 1.9.2, except for 
histological cirrhosis), all DILI events, and all major cardiovascular events: i.e., cardiovascular 
death, nonfatal myocardial infarction and stroke events as defined in the CEC chartermanual. 
The CEC will be comprised of 2 hepatologists, and 1 2 cardiologists and 1 endocrinologist, all 
of whom will be independent of the participants in the study. 
• 
Section 6.6.1 summary of safety data 
Text updated for consistency with current Investigator’s Brochure (Version 21). 
• 
Section 6.6.3 Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the 
therapeutic potential of elafibranor in metabolic diseases including NASH. Moreover, 
the Phase IIb trial demonstrated the efficacy of elafibranor at the therapeutic dose of 
120 mg on a clinically meaningful primary endpoint, resolution of histological NASH 
without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 


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was short and not designed for antifibrotic endpoints, it nonetheless showed that 
elafibranor, at 120 mg daily, improved fibrosis indirectly through the resolution of 
NASH. Importantly, elafibranor 120 mg concomitantly improved the cardiometabolic 
risk 
profile 
of 
the 
patients 
by 
decreasing 
plasma 
triglycerides, 
total 
and 
LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin 
resistance, and glucose homeostasis. Together these results position elafibranor as a 
drug candidate to treat NASH with the objective to block fibrosis evolution and 
ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns 
associated with elafibranor treatment, thus providing a favorable efficacy/safety 
profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring 
Board (DSMB) is to be established in order to review the safety of the treatment during 
the trial in an unblinded manner, to protect patient welfare and preserve study 
integrity. The safety assessments will be performed on a regular basis, every 6 months 
after Randomization of the first patient. The DSMB will consist of 5 experienced 
physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, and 
1 nephrologist) and 1 statistician, all independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring 
including assessment of many safety parameters and follow-up of the disease 
progression, mainly through noninvasive measures including FibroScan. 
• 
Section 7.2.2. Labeling 
Text amended to reflect updated regulations 
• 
Section 7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION 
Text amended for increased clarity  
Section 7.12.1. Handling of concomitant medication 
Text amended for increased clarity  
• 
Section 7.12.2. Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) 
Text amended for increased clarity and to reflect updates in inclusion/exclusion criteria and 
Appendix III 
• 
Section 7.12.3. Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) 
Text amended for increased clarity and to reflect updates in inclusion/exclusion criteria and 
Appendix III 
• 
Section 8.1.2. Serious adverse events 
• 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the 


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Investigator) to any study-specific procedure (e.g. wash out period, laboratory testing procedure, 
liver biopsy) must be reported as an SAE.  
• 
Section 8.1.2.2 Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays 
overnight in the hospital. An overnight stay is defined by hospitalization of 24 hours. 
Visits to the emergency room will not be considered hospital admission. 
• 
Section 8.1.3. Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation As 
an outcome event, progression to cirrhosis should not be included as an AE. 
• 
Section 8.3.1. Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient the last study visit. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and 
ends at study end for each patient the last study visit. 
• 
Section 8.3.2. Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit 
study end for each patient. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 
Events that are identified as potential primary efficacy endpoints for long-term evaluation will 
NOT be reported as SAEs unless it is determined by the adjudication committee that the event 
does not meet the predefined criteria for an endpoint. Events that are identified as potential 
primary efficacy endpoints for long-term evaluation that are not confirmed by adjudication will be 
reported as described with the start of the reporting time window being the time of negative 
adjudication decision. 
• 
Section 8.6.1. Pregnancy  
Text amended to add requirement for pregnant female partners to sign informed consent for 
pregnancy reporting 
• 
Section 9 Statistical methods and data analysis 
The first approved version of the SAP should be available within 3 months of protocol submission 
first patient randomized and before the first DSMB meeting. 
• 
Section 9.2.2 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on The long term endpoint of 
clinical outcomes described as is a composite endpoint composed of death due to any cause, liver 
cirrhosis, and the full list of portal hypertension/cirrhosis related events 


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• 
Section 9.5.1. Key secondary endpoint 
The analysis will be performed at the time of the interim analysis surrogate endpoint analysis 
when approximately 50% of patients (at least 1023) of patients with fibrosis stage F2 and F3 
have completed the 72 week treatment period or discontinued from the study. The null 
hypothesis will be tested at the two-sided 0.01 alpha level. 
• 
Section 9.5.2. Other secondary endpoints 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed 
terms for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured 
covariance matrix will be used for this analysis. The statistical model will be used to calculate the 
mean treatment difference and 95% confidence interval. If the data does not meet the required 
assumptions for parametric tests, the data will be analyzed using a nonparametric analysis of 
covariance method of Koch et al.37 Wilcoxon rank sum test. The median treatment difference 
and 95% confidence interval will be calculated using the Hodghes Lehmann method. 
• 
Section 9.8 Safety Analysis 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment 
group using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint 
and change from baseline will also be summarized using descriptive statistics. 
• 
Section 10.1. CRF Case report form and source documents  
Text amended for increased clarity 
• 
Appendix V 
Text amended to remove site number from wallet 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
Hepatocellular carcinoma 
• 
the onset of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis (SAF) 
activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory objectives 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and NAFLD 
Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 


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o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the tolerability and safety. 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver markers 
o 
renal biomarkers (including urinalysis) 
o 
cardiac biomarkers 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by a 
body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or 
homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement 
for presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is 
confirmed as well as any other event listed in the long-term composite endpoint, patients will be 
discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
• 
674 patients in placebo group  
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~250 centers 
Number of participating countries: ~25 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, 
Mexico, Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week-12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  


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o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented 
ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the patient)  
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
-Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at 
least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, 
and lobular inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of 
normal value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  
o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before Screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation). 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months 
prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver 
biopsy until the end of treatment. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c 
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal 
HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or 
positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease  
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
 
Concomitant medications: 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, 
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage 
has been kept constant for at least 2 months prior to Screening. 
19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
24. Positive anti-human immunodeficiency virus antibody. 
25. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients 
are allowed into the study. 
27. International normalized ratio >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 


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29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). 
31. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints  
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 


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o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – March 2017 
• 
Recruitment period: March 2016 – March 2018 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q4 2018 – Q1 2019 
• 
LPLV (LTTP): March 2022 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist all of whom will be 
independent of the participants in the study. 
 








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8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. In the LTTP the first ECG will be performed at V9 and then every 48. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively), 
and every 48 weeks thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 








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5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic and 
biomarker ICF. 
6. 
Visits SV1 and V1 should be scheduled at least 8 weeks apart in order to have 2 consecutive baseline values of AST, ALT, total bilirubin, and INR for DILI adjudication. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
AMENDMENT 1: 06 JANUARY 2017 ...................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 28 
TABLE OF CONTENTS ....................................................................................................................... 45 
TABLE OF TABLES ............................................................................................................................ 51 
TABLE OF FIGURES .......................................................................................................................... 51 
LIST OF ABBREVIATIONS .................................................................................................................. 52 
1. 
INTRODUCTION ................................................................................................................. 55 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 55 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 55 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 57 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 58 
1.4.1. 
Pharmacology .......................................................................................................... 58 
1.4.2. 
Safety pharmacology ................................................................................................ 58 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 58 
1.4.4. 
Toxicology ............................................................................................................... 60 
1.5. 
CLINICAL STUDIES ............................................................................................................. 61 
1.5.1. 
Phase I program ...................................................................................................... 61 
1.5.2. 
Phase II program ..................................................................................................... 62 
1.6. 
CONCLUSION ..................................................................................................................... 64 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 65 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 66 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 66 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 66 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) ............................... 66 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 67 
1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 67 
2. 
TRIAL OBJECTIVES ............................................................................................................. 69 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 69 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 69 


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2.1.2. 
Long-term endpoint ................................................................................................. 69 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS ................................... 69 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 70 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 70 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP ......................................................................... 71 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 71 
3. 
TRIAL DESIGN .................................................................................................................... 72 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 72 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 72 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 73 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 73 
3.5. 
STUDY PERIODS ................................................................................................................. 73 
3.6. 
SCREENING PERIOD ........................................................................................................... 73 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): ............... 73 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 75 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 75 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 75 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 76 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 76 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 77 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 78 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 78 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 79 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 80 
3.11. OPTIONAL VISITS .............................................................................................................. 81 
3.11.1. 
Retesting screening visits .......................................................................................... 81 
3.11.2. 
Unscheduled visits ................................................................................................... 81 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY ................................................................................. 81 
4. 
PATIENT SELECTION .......................................................................................................... 82 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 82 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 83 
5. 
TRIAL PROCEDURES ........................................................................................................... 86 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 86 
5.1.1. 
Standard diet and exercise recommendations ............................................................. 86 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 86 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 87 
5.1.4. 
Sun exposure .......................................................................................................... 87 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 87 
5.2.1. 
Handling of patient withdrawal .................................................................................. 87 


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5.2.2. 
Permanent discontinuations of study drug .................................................................. 87 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 88 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 89 
5.2.5. 
Replacement ........................................................................................................... 89 
5.2.6. 
Premature discontinuation of the study ...................................................................... 89 
5.3. 
PATIENT RESCREENING ...................................................................................................... 90 
6. 
ASSESSMENTS ................................................................................................................... 91 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 91 
6.1.1. 
Histological assessments ........................................................................................... 91 
6.1.2. 
Biological assessments ............................................................................................. 92 
6.1.3. 
Constitution of biobank ............................................................................................. 93 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 94 
6.2.1. 
Physical examination ................................................................................................ 94 
6.2.2. 
Waist circumference ................................................................................................. 94 
6.2.3. 
Vital signs ............................................................................................................... 94 
6.2.4. 
Electrocardiogram .................................................................................................... 95 
6.2.5. 
FibroScan ................................................................................................................ 95 
6.2.6. 
Quality of life questionnaire ...................................................................................... 95 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 95 
6.3.1. 
Creatine phosphokinase ............................................................................................ 95 
6.3.2. 
Liver function monitoring .......................................................................................... 96 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 97 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 98 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 98 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 98 
6.6.1. 
Summary of safety data............................................................................................ 98 
6.6.2. 
Safety data conclusion ............................................................................................ 100 
6.6.3. 
Benefit/risk assessment .......................................................................................... 101 
7. 
TREATMENTS ................................................................................................................... 102 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................ 102 
7.2. 
PACKAGING AND LABELING .............................................................................................. 102 
7.2.1. 
Packaging ............................................................................................................. 102 
7.2.2. 
Labeling ................................................................................................................ 102 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ....................................... 103 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................. 103 
7.5. 
STORAGE CONDITIONS .................................................................................................... 103 
7.6. 
DISPENSING OF TREATMENT ............................................................................................ 103 
7.7. 
TREATMENT REPLACEMENT .............................................................................................. 104 


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7.8. 
PROCEDURE FOR BLINDING .............................................................................................. 104 
7.9. 
PROCEDURE FOR UNBLINDING ......................................................................................... 104 
7.10. STUDY DRUG COMPLIANCE ............................................................................................... 105 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................ 105 
7.12. OTHER MEDICATION ........................................................................................................ 105 
7.12.1. 
Handling of concomitant medication ........................................................................ 105 
7.12.2. 
Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) ........................................................................................................... 106 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) ...................................................................... 106 
7.12.4. 
Permitted medication ............................................................................................. 107 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................. 108 
8.1. 
DEFINITIONS ................................................................................................................... 108 
8.1.1. 
Adverse events ...................................................................................................... 108 
8.1.2. 
Serious adverse events ........................................................................................... 109 
8.1.3. 
Clarification on serious adverse events: .................................................................... 110 
8.1.4. 
Adverse drug reaction ............................................................................................ 111 
8.1.5. 
Unexpected adverse event ...................................................................................... 111 
8.2. 
ASSESSMENTS ................................................................................................................. 111 
8.2.1. 
Intensity assessment .............................................................................................. 111 
8.2.2. 
Relation to the study treatment ............................................................................... 112 
8.2.3. 
Action taken and outcome ...................................................................................... 112 
8.3. 
REPORTING ..................................................................................................................... 113 
8.3.1. 
Reporting an adverse event .................................................................................... 113 
8.3.2. 
Reporting a serious adverse event ........................................................................... 113 
8.3.3. 
Follow-up .............................................................................................................. 115 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 115 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 115 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 116 
8.6.1. 
Pregnancy ............................................................................................................. 116 
8.6.2. 
Medication error..................................................................................................... 116 
8.6.3. 
Misuse .................................................................................................................. 116 
8.6.4. 
Overdose .............................................................................................................. 117 
8.6.5. 
Abuse ................................................................................................................... 117 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 118 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 118 
9.2. 
ENDPOINTS ..................................................................................................................... 118 
9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 118 


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9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 118 
9.2.3. 
Key Secondary Endpoint ......................................................................................... 119 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 119 
9.2.5. 
Exploratory endpoints ............................................................................................. 120 
9.3. 
ANALYSIS SETS ................................................................................................................ 120 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 121 
9.4.1. 
Resolution of NASH ................................................................................................ 121 
9.4.2. 
Long-term endpoints .............................................................................................. 121 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 122 
9.5.1. 
Key secondary endpoint.......................................................................................... 122 
9.5.2. 
Other secondary endpoints ..................................................................................... 122 
9.5.3. 
Subgroup analyses ................................................................................................. 122 
9.5.4. 
Exploratory analyses .............................................................................................. 123 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 123 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 123 
9.7.1. 
Resolution of NASH ................................................................................................ 123 
9.7.2. 
Time to clinical event/death .................................................................................... 124 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 124 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 125 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 125 
10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 126 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 126 
10.2. RETENTION OF RECORDS ................................................................................................. 126 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 128 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 128 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 129 
11.3. QUALITY ASSURANCE ....................................................................................................... 129 
12. 
ETHICS AND REGULATORY................................................................................................ 130 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 130 
12.2. COMPETENT AUTHORITY .................................................................................................. 131 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 131 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 131 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 132 
13. 
FINANCING AND INSURANCE ............................................................................................ 133 
13.1. FINANCIAL ISSUES ........................................................................................................... 133 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 133 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 134 
14.1. STUDY REPORT ................................................................................................................ 134 


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14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 134 
15. 
REFERENCES LIST ............................................................................................................ 136 
APPENDICES .................................................................................................................................. 139 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 140 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 148 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 149 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 151 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 152 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
35 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
39 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
99 
 
 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
43 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
44 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 


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GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 


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SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 


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proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 


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macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver.  
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
 Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 


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the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
elafibranor (GFT505) has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 


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1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 


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1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 621 volunteers were randomized in 
these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 
volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 


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The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180, and 240 mg of elafibranor, and the time dependency of the PK parameters 
after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 
treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 


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tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 
(-20% to -35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 


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high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C, and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia, and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 
these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 


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resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 


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Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 
fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint).  


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Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 


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in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 
will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 


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2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire) 
• 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed 
in the composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674  patients) 
treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with at least 2 
of the following conditions: persistent elevated (absence of normal ALT within the past year, obesity 
defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education Program’s 
Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also be 
enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 


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• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an 
event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 


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• 
Physical examination (described in Section 6.2.1). 
• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, an additional SV2 visit will be booked at 
least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
Visits SV1 and V1 should be scheduled at least 8 weeks apart in order to have 2 consecutive baseline 
values of AST, ALT, total bilirubin, and INR for DILI adjudication (using SV1 and V1 kits). 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 30, and 31 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 
 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, an additional SV2 visit will be booked by at 
least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood samples for 
coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver biopsy. 
Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), a surrogate endpoint 
analysis will be performed and potentially filed for initial market approval under Subpart H or conditional 
approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 


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• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.5) 
• 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, 
death due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 


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3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 
1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the Investigator may 
decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed 
for each phone visit. 


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3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2), 
• 
Urinary pregnancy test (for WOCBP only)  
• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 


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3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
the onset of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
 ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 


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 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to 
Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, 
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like 
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on 
stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 


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19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
24. Positive anti-human immunodeficiency virus (HIV) antibody. 
25. AST and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
27. INR >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 
29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
31. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle 
recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 7 days. 
• 
On each study visit day, study treatment will be taken under fasting conditions after the blood 
sampling (which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 


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• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1) 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 


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Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 


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and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 


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5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 
the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site.  
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 
24 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, 
signed, and dated by the Investigator as soon as they are received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 
3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3).  
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 
6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel to 
the floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 
80% of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the 
LTTP under 2 hour fasting conditions. Where possible, FibroScan must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.  
In case of result ≥14 kPa or of sudden increase from previous measurement, a repeated measurement will 
be required 4 weeks later (to be performed at an unscheduled visit). 
If at baseline, the measurement gives a value ≥14 kPa but without being associated with confirmed 
histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but will not be 
used for the detection of cirrhosis (no repeat test required for patients with baseline≥14 kPa at V1). 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 
3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 


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If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN.  
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC Charter). 
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5: permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 


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• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study drug and 
schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (calculated NAFLD fibrosis >0.676 score or reported FIB-4 >2.67). 
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 


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6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. A 
detailed description of the interim analysis procedures and decision-making process will be provided in the 
DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 
1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist, all of whom will be 
independent of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 621 volunteers were randomized 
in these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety 
of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 69 SAEs that have been reported cumulatively in the clinical development program, 48 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. For all SAEs, the 
treatment code has been broken (end of study unblinding). 


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Of the 48 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the investigators (serious adverse reaction). They consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in 
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
For 3 of the cases (atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease) after 
later investigations, given the medical history of the patients or the time of occurrence of the event, 
relationship to elafibranor was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal disorders  
Nausea 
Mild to severe 
4.4% 
Diarrhea  
Mild to moderate 
3.3% 
Vomiting 
Mild to moderate 
1.6% 
General disorders and administration site 
conditions  
Fatigue 
Mild to moderate 
1.9% 
Asthenia  
Mild to moderate 
1.1% 
Investigations  
Hepatic enzymes increased (mainly 
transaminases) 
Mild to severe 
1.8% 
Blood creatine phosphokinase increased 
Mild to moderate 
1.1% 
Musculoskeletal and connective tissue 
disorders  
Myalgia 
Mild to severe 
1.6% 
Metabolism & nutrition disorders  
Decrease appetite 
Mild to severe 
1.6% 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 
1.2% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.2% 
 


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Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
based on creatinine). Myalgia, decrease of appetite and hot flush were also reported in more than 1% of 
patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI.  
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014).  
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study between 
elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods during clinical 
trials should be avoided, and they should be accompanied by barrier methods. 
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as nausea, diarrhea 
and vomiting, and asthenia or fatigue are considered common and expected adverse reactions reasonably 
associated with elafibranor. Most of them are of mild to moderate intensity. As previously, laboratory 
increases of serum creatinine or CPK should be monitored throughout clinical trials as this has been 
observed in Phase II trials, and is a known PPARα agonist effect. Elevation of AT will be monitored as well 
as DILI. In the absence of human pregnancy data, double contraception should be maintained for women 


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of childbearing potential participating in clinical trials with elafibranor treatment, up to 1 month after end of 
study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 
objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is to be 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis, every 6 months after Randomization of the first patient. The DSMB will consist of 5 experienced 
physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 
1 statistician, all independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: Product carton and wallet labeling 
. 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and 
ensure the study drug is at site for the visits occurring. The IXRS will continue to project study drug 
requirements per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond 
to the number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number 
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available 
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the 
entered treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling) 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II, 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 
within 6 months prior to Screening) and information should be communicated to the Medical Monitor in 


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order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” 
basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I, 
APPENDIX 
III: 
Permitted/non-permitted medication) 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 
weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
Ursodeoxycholic acid. 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE.  
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 


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not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 


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• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 


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• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 


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Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient. Whenever possible, symptoms 
should be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, 
maximal intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) 
and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall 
pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN 
fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the surrogate efficacy analysis when at least 1023 of the F2 to F3 patients 
complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 for details). 
An additional exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 


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• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the surrogate endpoint analysis (at least 1023 
patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 


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o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 


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Patients in the ITT, FITT, PPS, and exploratory F1 cohorts (study population and efficacy data) will 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 99% confidence interval. The main confirmatory analysis will be performed 
when at least 1023 F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death and time to first 
cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s model, log 
rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 


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Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the 
surrogate endpoint analysis when at least 1023 of patients with fibrosis stage F2 and F3 have completed 
the 72 week treatment period or discontinued from the study. The null hypothesis will be tested at the 
two-sided 0.01 alpha level. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 
data will be analyzed using a nonparametric analysis of covariance method of Zink and Koch.37 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
Presence of type 2 diabetes (yes, no) 
 
Gender (male, female) 


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• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the 
primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided 
α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.01. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 


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The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 


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Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics.  
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when 1023 F2 and F3 patients 
complete 72 weeks of treatment or discontinue early from the study. The null hypothesis will be tested at 
the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target 
number of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
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Gastroenterol Hepatol. 2009;7(2):234-328. 
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35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
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Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
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Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 
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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
3.0 
DATE: 
April 03, 2017 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
  
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
ePRO 
 
 
 
 
 
 
 
 


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AMENDMENT 2: 2017 
Amendment 2 is a non substantial change to clarify the collection of 2 baseline values of liver enzymes before study treatment initiation. This remains in line 
with the FDA request to obtain 2 baseline values of liver transaminase, total bilirubin, and INR at least 8 weeks apart, in order to be able to have 2 baseline 
values in case of DILI adjudication.  Added text is bolded; deleted text is struck through. 
Summary of changes to the protocol: 
Section 
New Text 
Table 1: 
 STUDY GENERAL 
ASSESSMENT 
SCHEDULE 
Table 1 updated with changes related to the screening period 
 
 
4. 
The visits to be performed during the screening period should be scheduled according to  the following 
requirements:  
- 
If there are historical lab values for AST, ALT, total bilirubin and INR that are within 8 
weeks to 6 months of the planned Randomization visit (V1) these results can be used 
as the first baseline values in case of DILI adjudication. If there are no historical lab 
values that meet this requirement, then SV1 and V1 must be scheduled at least 8 
weeks apart. 
- 
This The visit SV2 only occurs if no historical biopsy within 6 months before the Screening Visit is available. A 


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Section 
New Text 
screening liver biopsy and slides shipment to the central pathologist must be performed at least 4 weeks 
before Randomization,(in order to obtain the results in time). However, in some exceptional cases, the 
central reading process can be expedited allowing a shorter time between SV1 or SV2 and V1. 
Coagulation (platelet count and PT [INR]) should be checked locally prior to this liver biopsy (according to 
local medical standards in each hospital). 
- 
Randomization visit can be scheduled as soon as all the results are available to confirm the 
eligibility of the patients 
 
Table 2: 
STUDY BIOLOGICAL 
ASSESSMENT 
SCHEDULE  
Table 2 updated with changes related to the screening period 
 
6. 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 
8 weeks to 6 months of planned randomization visit (V1) are available, then SV1 and V1 must 
be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI 
adjudication. In any case, the visits should be scheduled in order to obtain the needed results prior to 
the randomization. 
 
Figure 1:  
STUDY DURATION 
AND VISIT 
SCHEDULE 
Figure updated with changes related to the screening period 


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Section 
New Text 
 
Figure 2:  
PREGNANCY 
Figure updated with changes related to the screening period 


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Section 
New Text 
TESTING SCHEDULE 
FOR WOMEN OF 
CHILDBEARING 
POTENTIAL 
 
Section 3.6.1 
3.6 - SCREENING PERIOD (WEEK -12 TO WEEK -1) 
 
3.6.1 - Screening visits SV1 (Week 12 to Week 8) and SV2 (Week 12 to Week 4): 
 


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 3 . 0 0 3 A pril 2 0 1 7  
G E N F I T  
C O N FI D E N TI A L  
P a g e 1 3  of 1 4 0  
S e cti o n  
N e w T e xt  
T h e f oll o wi n g s cr e e ni n g pr o c e d ur es will b e p erf or m e d f or all p ot e nti al p ati e nts at S V 1 c o n d u ct e d b et w e e n  d uri n g t h e 
s cr e e ni n g p eri o d a n d pri or t o r a n d o mi z ati o n  W e e k 
1 2 a n d W e e k 8 pri or t o R a n d o miz ati o n : 
 
•  
Si g n at ur e  of  i nf or m e d  c o ns e nt  wit n ess e d  b y  t h e  I n v esti g at or  or  d esi g n at e d  p ers o n. N ot e :  T h e  si g n at ur e  of  t h e 
i nf or m e d c o ns e nt m a y als o b e p erf or m e d b ef or e S V 1. 
•  
P ati e nt n u m b er all o c ati o n vi a I X R S.  
•  
C h e c k m e di c al hist or y/ d e m o gr a p hi cs.  
•  
C h e c k i n cl usi o n/ e x cl usi o n crit eri a ( d es cri b e d i n S e cti o n  4) . 
•  
P h ysi c al e x a mi n ati o n ( d es cri b e d i n S e cti o n  6. 2. 1 ). 
•  
A d e q u at e  di et  r e c o m m e n d ati o ns  ( d es cri b e d  i n  S e cti o n 5. 1. 1  a n d A P P E N DI X  II:  A d e q u at e  di et  a n d  lif est yl e 
r e c o m m e n d ati o ns), al c o h ol r estri cti o ns ( d es cri b e d i n S e cti o n 5. 1. 2 ), a n d t o b a c c o h a bits. 
•  
R e c or d vit al si g ns ( d es cri b e d i n S e cti o n  6. 2. 3 ). 
•  
R e c or d h ei g ht, w ei g ht, a n d w aist cir c u mf er e n c e.  
•  
C h e c k c o n c o mit a nt/ pri or m e di c ati o n ( wit hi n 6 m o nt hs pri or t o S cr e e ni n g) ( d es cri b e d i n S e cti o n  7. 1 2  a n d  A P P E N DI X 
III: P er mitt e d/ n o n-p er mitt e d m e di c ati o n ) 
•  
C h e c k  if  a  li v er  bi o ps y  wit h  c o nfir m e d  N A S H  a n d  fi br osis  is  a v ail a bl e,  a n d,  if  s o  s e n d  s a m pl e  f or  c e ntr al 
c o nfir m ati o n of N A S H di a g n osis ( d es cri b e d i n S e cti o n  6. 1. 1. 2 ). T his hist ori c al di a g n osti c bi o ps y s h o ul d b e o bt ai n e d 
wit hi n 6 m o nt hs pri or t o t h e S cr e e ni n g Visit.  
•  
C h e c k A Es fr o m ti m e of I nf or m e d C o ns e nt F or m (I C F) si g n at ur e ( d es cri b e d i n S e cti o n  6 a n d S e cti o n  8 ). 
T h e S cr e e ni n g bi ol o gi c al ass ess m e nt ( S B 1 will b e s c h e d ul e d at S V 1).  
If n o di a g n osti c li v er bi o ps y ( wit hi n 6 m o nt hs of S V 1) is a v ail a bl e, it i s r e c o m m e n d e d t o s c h e d ul e a n a d diti o n al S V 2 
visit will  b e b o o k e d  at l e ast W e e k -4 ( p eri o d b et w e e n S cr e e ni n g a n d W e e k 4)  pri or t o t h e pl a n n e d R a n d o miz ati o n V 1, i n 
or d er t o o bt ai n t h e r e s ult s i n ti m e .  
 
T h e f oll o wi n g bi ol o gi c al ass ess m e nts ( d et ail e d i n T a bl e 2) will b e p erf or m e d at S B 1:  
 Bl o o d s a m pl es ( d es cri b e d i n T a bl e 2).  
 W h ol e bl o o d, pl as m a & s er u m b a n k s a m pl es ( o nl y if a d diti o n al g e n eti c a n d bi o m ar k er I C F si g n e d).  


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 3 . 0 0 3 A pril 2 0 1 7  
G E N F I T  
C O N FI D E N TI A L  
P a g e 1 4  of 1 4 0  
S e cti o n  
N e w T e xt  
 Uri n al ysis di psti c k.  
 Uri n ar y pr e g n a n c y t est (f or w o m e n of c hil d b e ari n g p ot e nti al o nl y [ W O C B P]).  
 
If n o hi st ori c al v al u e s of A S T, A L T, t ot al bilir u bi n a n d I N R m e eti n g t h e r e q uir e m e nt s of wit hi n 8 w e e k s t o 6 
m o nt h s of r a n d o mi z ati o n vi sit ar e a v ail a bl e, t h e n S V 1 a n d V 1 m u st b e s c h e d ul e d at l e a st 8 w e e k s a p art i n 
or d er t o h a v e 2 c o n s e c uti v e v al u e s f or D I L I a dj u di c ati o n.  
Visits S V 1 a n d V 1 s h o ul d b e s c h e d ul e d at l e ast 8 w e e ks a p art i n or d er t o h a v e 2 c o ns e c uti v e b as eli n e v al u es of A S T, A L T, 
t ot al bilir u bi n, a n d I N R f or DI LI a dj u di c ati o n ( usi n g S V 1 a n d V 1 kits).  
 
S e cti o n 3. 6. 2  
3. 6. 2 - S cr e e ni n g Visit S V 2 (li v er bi o ps y if r e q uir e d, W e e k -1 2 t o r e c o m m e n d e d W e e k -4):  
If n o di a g n osti c li v er bi o ps y wit hi n 6 m o nt hs of S V 1 is a v ail a bl e, it i s r e c o m m e n d e d t o s c h e d ul e a n a d diti o n al S V 2 visit 
will b e b o o k e d b y  at l e ast W e e k -4 f or a li v er bi o ps y t o b e p erf or m e d ( d es cri b e d i n S e cti o n 6. 1. 1. 1). Bl o o d s a m pl es f or 
c o a g ul ati o n ( d et ail e d i n T a bl e 2) will b e t a k e n a n d t est e d at a l o c al l a b or at or y pri or t o t h e li v er bi o ps y. Li v er bi o ps y 
s a m pl es will b e s e nt f or c e ntr al  c o nfir m ati o n of N A S H di a g n osis ( d es cri b e d i n S e cti o n 6. 1. 1. 2).  
 
S e cti o n 6. 3. 2  
6. 3. 2 -Li v er f u n cti o n m o nit ori n g  
 
All li v er d e c o m p e ns ati o n e v e nts i n cl u d e d i n t h e c o m p osit e effi c a c y e n d p oi nt ( S e cti o n 1. 9. 2) will b e a dj u di c at e d b y t h e 
Cli ni c al E v e nts C o m mitt e e ( C E C; s e e S e cti o n 6. 5), as w ell as all DI LI e v e nts (s e e S e cti o n 6. 5).  
F or D I L I a dj u di c ati o n, a s s e s s m e nt m a y b e p erf or m e d u si n g a s b a s eli n e eit h er hi st ori c al A S T, A L T, t ot al 
bilir u bi n, a n d I N R r e s ult s m e eti n g t h e r e q uir e m e nt s of wit hi n 8 w e e k s t o 6 m o nt h s of pl a n n e d 
r a n d o mi z ati o n vi sit ( V 1), or, u si n g l a b r e s ult s fr o m S V 1 a n d V 1 t h at ar e at l e a st 8 w e e k s a p art.  F or DI LI 
a dj u di c ati o n, ass ess m e nt m a y b e p erf or m e d usi n g as b as eli n e v al u e t h e a v er a g e o bt ai n e d fr o m m e as ur e m e nts at t h e S V 1 
a n d V 1 visits ( d es cri b e d i n t h e C E C C h art er).   
I n  all  c as es,  w h et h er  b as eli n e  A T  v al u es  ar e  n or m al  or  el e v at e d,  a n  i n cr e as e  of  A T  > 1 0  x  U L N  will  l e a d  t o  p er m a n e nt 
dis c o nti n u ati o n of t h e p ati e nt fr o m st u d y dr u g, a n d s c h e d uli n g of E O T visit ( S e cti o n 3. 9 ). 


Clinical Trial GFT505-315-1  
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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
Hepatocellular carcinoma 
• 
the onset of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis (SAF) 
activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory objectives 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and NAFLD 
Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 


Clinical Trial GFT505-315-1  
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o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the tolerability and safety. 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver markers 
o 
renal biomarkers (including urinalysis) 
o 
cardiac biomarkers 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by a 
body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or 
homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement 
for presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is 
confirmed as well as any other event listed in the long-term composite endpoint, patients will be 
discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
• 
674 patients in placebo group  
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~250 centers 
Number of participating countries: ~25 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, 
Mexico, Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week -12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  


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o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented 
ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the patient)  
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
-Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at 
least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, 
and lobular inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of 
normal value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  
o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before Screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation). 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months 
prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver 
biopsy until the end of treatment. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c 
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal 
HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or 
positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease  
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
 
Concomitant medications: 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, 
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage 
has been kept constant for at least 2 months prior to Screening. 
19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
24. Positive anti-human immunodeficiency virus antibody. 
25. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients 
are allowed into the study. 
27. International normalized ratio >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 


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29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). 
31. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints  
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 


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o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – March 2017 
• 
Recruitment period: March 2016 – March 2018 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q4 2018 – Q1 2019 
• 
LPLV (LTTP): March 2022 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist all of whom will be 
independent of the participants in the study. 
 








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- 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the patients 
5. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to 
Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. In the LTTP the first ECG will be performed at V9 and then every 48. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively), 
and every 48 weeks thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 
 








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5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic 
and biomarker ICF. 
6. 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1) are 
available, then SV1 and V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits 
should be scheduled in order to obtain the needed results prior to the randomization. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
AMENDMENT 2: 2017 ......................................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 15 
TABLE OF CONTENTS ....................................................................................................................... 32 
TABLE OF TABLES ............................................................................................................................ 38 
TABLE OF FIGURES .......................................................................................................................... 39 
LIST OF ABBREVIATIONS .................................................................................................................. 40 
1. 
INTRODUCTION ................................................................................................................. 43 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 43 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 43 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 45 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 46 
1.4.1. 
Pharmacology .......................................................................................................... 46 
1.4.2. 
Safety pharmacology ................................................................................................ 46 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 46 
1.4.4. 
Toxicology ............................................................................................................... 48 
1.5. 
CLINICAL STUDIES ............................................................................................................. 49 
1.5.1. 
Phase I program ...................................................................................................... 49 
1.5.2. 
Phase II program ..................................................................................................... 50 
1.6. 
CONCLUSION ..................................................................................................................... 52 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 53 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 54 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 54 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 54 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) ............................... 54 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 55 
1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 55 
2. 
TRIAL OBJECTIVES ............................................................................................................. 57 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 57 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 57 


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2.1.2. 
Long-term endpoint ................................................................................................. 57 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS ................................... 57 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 58 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 58 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP ......................................................................... 59 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 59 
3. 
TRIAL DESIGN .................................................................................................................... 60 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 60 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 60 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 61 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 61 
3.5. 
STUDY PERIODS ................................................................................................................. 61 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) ...................................................................... 61 
3.6.1. 
Screening visits SV1 and SV2 .................................................................................... 61 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): ....... 63 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 63 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 63 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 64 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 64 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 65 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 66 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 67 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 67 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 68 
3.11. OPTIONAL VISITS .............................................................................................................. 69 
3.11.1. 
Retesting screening visits .......................................................................................... 69 
3.11.2. 
Unscheduled visits ................................................................................................... 69 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY ................................................................................. 69 
4. 
PATIENT SELECTION .......................................................................................................... 70 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 70 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 71 
5. 
TRIAL PROCEDURES ........................................................................................................... 74 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 74 
5.1.1. 
Standard diet and exercise recommendations ............................................................. 74 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 74 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 75 
5.1.4. 
Sun exposure .......................................................................................................... 75 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 75 
5.2.1. 
Handling of patient withdrawal .................................................................................. 75 


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5.2.2. 
Permanent discontinuations of study drug .................................................................. 75 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 76 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 77 
5.2.5. 
Replacement ........................................................................................................... 77 
5.2.6. 
Premature discontinuation of the study ...................................................................... 77 
5.3. 
PATIENT RESCREENING ...................................................................................................... 78 
6. 
ASSESSMENTS ................................................................................................................... 79 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 79 
6.1.1. 
Histological assessments ........................................................................................... 79 
6.1.2. 
Biological assessments ............................................................................................. 80 
6.1.3. 
Constitution of biobank ............................................................................................. 81 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 82 
6.2.1. 
Physical examination ................................................................................................ 82 
6.2.2. 
Waist circumference ................................................................................................. 82 
6.2.3. 
Vital signs ............................................................................................................... 82 
6.2.4. 
Electrocardiogram .................................................................................................... 83 
6.2.5. 
FibroScan ................................................................................................................ 83 
6.2.6. 
Quality of life questionnaire ...................................................................................... 83 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 83 
6.3.1. 
Creatine phosphokinase ............................................................................................ 83 
6.3.2. 
Liver function monitoring .......................................................................................... 84 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 85 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 86 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 86 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 86 
6.6.1. 
Summary of safety data............................................................................................ 86 
6.6.2. 
Safety data conclusion .............................................................................................. 88 
6.6.3. 
Benefit/risk assessment ............................................................................................ 89 
7. 
TREATMENTS ..................................................................................................................... 90 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS .............................................................................. 90 
7.2. 
PACKAGING AND LABELING ................................................................................................ 90 
7.2.1. 
Packaging ............................................................................................................... 90 
7.2.2. 
Labeling .................................................................................................................. 90 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ......................................... 91 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 91 
7.5. 
STORAGE CONDITIONS ...................................................................................................... 91 
7.6. 
DISPENSING OF TREATMENT .............................................................................................. 91 
7.7. 
TREATMENT REPLACEMENT ................................................................................................ 92 


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7.8. 
PROCEDURE FOR BLINDING ................................................................................................ 92 
7.9. 
PROCEDURE FOR UNBLINDING ........................................................................................... 92 
7.10. STUDY DRUG COMPLIANCE ................................................................................................. 93 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. .......................................... 93 
7.12. OTHER MEDICATION .......................................................................................................... 93 
7.12.1. 
Handling of concomitant medication .......................................................................... 93 
7.12.2. 
Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) ............................................................................................................. 94 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) ........................................................................ 94 
7.12.4. 
Permitted medication ............................................................................................... 95 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 96 
8.1. 
DEFINITIONS ..................................................................................................................... 96 
8.1.1. 
Adverse events ........................................................................................................ 96 
8.1.2. 
Serious adverse events ............................................................................................. 97 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 98 
8.1.4. 
Adverse drug reaction .............................................................................................. 99 
8.1.5. 
Unexpected adverse event ........................................................................................ 99 
8.2. 
ASSESSMENTS ................................................................................................................... 99 
8.2.1. 
Intensity assessment ................................................................................................ 99 
8.2.2. 
Relation to the study treatment ............................................................................... 100 
8.2.3. 
Action taken and outcome ...................................................................................... 100 
8.3. 
REPORTING ..................................................................................................................... 101 
8.3.1. 
Reporting an adverse event .................................................................................... 101 
8.3.2. 
Reporting a serious adverse event ........................................................................... 101 
8.3.3. 
Follow-up .............................................................................................................. 103 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 103 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 103 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 104 
8.6.1. 
Pregnancy ............................................................................................................. 104 
8.6.2. 
Medication error..................................................................................................... 104 
8.6.3. 
Misuse .................................................................................................................. 104 
8.6.4. 
Overdose .............................................................................................................. 105 
8.6.5. 
Abuse ................................................................................................................... 105 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 106 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 106 
9.2. 
ENDPOINTS ..................................................................................................................... 106 
9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 106 


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9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 106 
9.2.3. 
Key Secondary Endpoint ......................................................................................... 107 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 107 
9.2.5. 
Exploratory endpoints ............................................................................................. 108 
9.3. 
ANALYSIS SETS ................................................................................................................ 108 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 109 
9.4.1. 
Resolution of NASH ................................................................................................ 109 
9.4.2. 
Long-term endpoints .............................................................................................. 109 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 110 
9.5.1. 
Key secondary endpoint.......................................................................................... 110 
9.5.2. 
Other secondary endpoints ..................................................................................... 110 
9.5.3. 
Subgroup analyses ................................................................................................. 110 
9.5.4. 
Exploratory analyses .............................................................................................. 111 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 111 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 111 
9.7.1. 
Resolution of NASH ................................................................................................ 111 
9.7.2. 
Time to clinical event/death .................................................................................... 112 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 112 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 113 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 113 
10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 114 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 114 
10.2. RETENTION OF RECORDS ................................................................................................. 114 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 116 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 116 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 117 
11.3. QUALITY ASSURANCE ....................................................................................................... 117 
12. 
ETHICS AND REGULATORY................................................................................................ 118 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 118 
12.2. COMPETENT AUTHORITY .................................................................................................. 119 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 119 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 119 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 120 
13. 
FINANCING AND INSURANCE ............................................................................................ 121 
13.1. FINANCIAL ISSUES ........................................................................................................... 121 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 121 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 122 
14.1. STUDY REPORT ................................................................................................................ 122 


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14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 122 
15. 
REFERENCES LIST ............................................................................................................ 124 
APPENDICES .................................................................................................................................. 127 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 128 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 136 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 137 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 139 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 140 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
22 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
26 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
87 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
30 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
31 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 


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GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 


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SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 


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proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 


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macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver.  
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
 Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 


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the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
elafibranor (GFT505) has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 


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1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 


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1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 621 volunteers were randomized in 
these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 
volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 


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The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180, and 240 mg of elafibranor, and the time dependency of the PK parameters 
after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 
treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 


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tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides (-20% to 
-35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, insulin-
resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic dyslipidemia). In 
addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins (ApoAI and 
ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 


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high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C, and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia, and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 
these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 


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resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 


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Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 
fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint).  


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Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 


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in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 
will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 


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2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire) 
• 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed 
in the composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674  patients) 
treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with at least 2 
of the following conditions: persistent elevated (absence of normal ALT within the past year, obesity 
defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education Program’s 
Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also be 
enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 


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• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an 
event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) 
3.6.1. 
Screening visits SV1 and SV2  
The following screening procedures will be performed for all potential patients at SV1 conducted during the 
screening period and prior to randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 
• 
Physical examination (described in Section 6.2.1). 


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• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an 
additional SV2 visit at least Week -4  prior to the planned Randomization V1, in order to obtain the results 
in time. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 
months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart in 
order to have 2 consecutive values for DILI adjudication.   
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 30, and 31 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 


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 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 
A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended 
Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an 
additional SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 


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During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 
At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), a surrogate endpoint 
analysis will be performed and potentially filed for initial market approval under Subpart H or conditional 
approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 


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• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see  
Figure 2]) since previous visit (for WOCBP only, every visit from V1)   
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.5) 
• 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, 
death due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 


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At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 
1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see  
Figure 2]) since previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 


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3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the Investigator may 
decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed 
for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2), 
• 
Urinary pregnancy test (for WOCBP only)  


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• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 


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o 
the onset of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
 ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to 
Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, 
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like 
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on 
stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 


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19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
24. Positive anti-human immunodeficiency virus (HIV) antibody. 
25. AST and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
27. INR >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 
29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
31. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle 
recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 7 days. 
• 
On each study visit day, study treatment will be taken under fasting conditions after the blood 
sampling (which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 


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• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1) 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 


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Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 


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and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 


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5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 
the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site.  
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 
24 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, 
signed, and dated by the Investigator as soon as they are received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 
3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3).  
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 
6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel to 
the floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 
80% of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the 
LTTP under 2 hour fasting conditions. Where possible, FibroScan must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.  
In case of result ≥14 kPa or of sudden increase from previous measurement, a repeated measurement will 
be required 4 weeks later (to be performed at an unscheduled visit). 
If at baseline, the measurement gives a value ≥14 kPa but without being associated with confirmed 
histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but will not be 
used for the detection of cirrhosis (no repeat test required for patients with baseline≥14 kPa at V1). 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 
3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 


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If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN.  
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned 
randomization visit (V1), or, using lab results from SV1 and  V1 that are at least 8 weeks apart.  
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5: permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 


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• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study drug and 
schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (calculated NAFLD fibrosis >0.676 score or reported FIB-4 >2.67). 
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 


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6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. A 
detailed description of the interim analysis procedures and decision-making process will be provided in the 
DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 
1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist, all of whom will be 
independent of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 621 volunteers were randomized 
in these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety 
of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 69 SAEs that have been reported cumulatively in the clinical development program, 48 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. For all SAEs, the 
treatment code has been broken (end of study unblinding). 


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Of the 48 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the investigators (serious adverse reaction). They consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in 
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
For 3 of the cases (atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease) after 
later investigations, given the medical history of the patients or the time of occurrence of the event, 
relationship to elafibranor was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal disorders  
Nausea 
Mild to severe 
4.4% 
Diarrhea  
Mild to moderate 
3.3% 
Vomiting 
Mild to moderate 
1.6% 
General disorders and administration site 
conditions  
Fatigue 
Mild to moderate 
1.9% 
Asthenia  
Mild to moderate 
1.1% 
Investigations  
Hepatic enzymes increased (mainly 
transaminases) 
Mild to severe 
1.8% 
Blood creatine phosphokinase increased 
Mild to moderate 
1.1% 
Musculoskeletal and connective tissue 
disorders  
Myalgia 
Mild to severe 
1.6% 
Metabolism & nutrition disorders  
Decrease appetite 
Mild to severe 
1.6% 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 
1.2% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.2% 
 


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Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
based on creatinine). Myalgia, decrease of appetite and hot flush were also reported in more than 1% of 
patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI.  
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014)34.  
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study between 
elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods during clinical 
trials should be avoided, and they should be accompanied by barrier methods. 
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as nausea, diarrhea 
and vomiting, and asthenia or fatigue are considered common and expected adverse reactions reasonably 
associated with elafibranor. Most of them are of mild to moderate intensity. As previously, laboratory 
increases of serum creatinine or CPK should be monitored throughout clinical trials as this has been 
observed in Phase II trials, and is a known PPARα agonist effect. Elevation of AT will be monitored as well 
as DILI. In the absence of human pregnancy data, double contraception should be maintained for women 


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of childbearing potential participating in clinical trials with elafibranor treatment, up to 1 month after end of 
study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 
objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is to be 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis, every 6 months after Randomization of the first patient. The DSMB will consist of 5 experienced 
physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 
1 statistician, all independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: Product carton and wallet labeling 
. 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and 
ensure the study drug is at site for the visits occurring. The IXRS will continue to project study drug 
requirements per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond 
to the number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number 
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available 
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the 
entered treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling 
• 
) 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II, 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 


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within 6 months prior to Screening) and information should be communicated to the Medical Monitor in 
order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” 
basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I, 
APPENDIX 
III: 
Permitted/non-permitted medication) 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 
weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
Ursodeoxycholic acid. 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE.  
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 


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not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 


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• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 


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• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 


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Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient. Whenever possible, symptoms 
should be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, 
maximal intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) 
and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall 
pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN 
fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the surrogate efficacy analysis when at least 1023 of the F2 to F3 patients 
complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 for details). 
An additional exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 


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• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the surrogate endpoint analysis (at least 1023 
patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 


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o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 


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Patients in the ITT, FITT, PPS, and exploratory F1 cohorts (study population and efficacy data) will 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 99% confidence interval. The main confirmatory analysis will be performed 
when at least 1023 F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death and time to first 
cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s model, log 
rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 


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Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the 
surrogate endpoint analysis when at least 1023 of patients with fibrosis stage F2 and F3 have completed 
the 72 week treatment period or discontinued from the study. The null hypothesis will be tested at the 
two-sided 0.01 alpha level. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 
data will be analyzed using a nonparametric analysis of covariance method of Zink and Koch.37 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 


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• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the 
primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided 
α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.01. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 


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The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 


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Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics.  
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when 1023 F2 and F3 patients 
complete 72 weeks of treatment or discontinue early from the study. The null hypothesis will be tested at 
the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target 
number of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santibanez C, Haim D, et al. Enhancement in liver nuclear factor-kb (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-
acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. Epub 
2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al. Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
Trials Using Cox Proportional Hazards Models and Nonparametric Randomization Based 
Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
37. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 
.  
 


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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 






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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
Protocol N°: 
 
GFT505-315-1 / EudraCT N° 2015-005385-38/ IND n°115028 
Version number: 
4.0 
Release date:  
03 January 2020 
TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
In signing below, I give agreement to the protocol. 
  
 
____
________________ 
 
 
_____ 
Signature 
Date (dd-mmm-yyyy) 






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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
4.0 
DATE: 
03 January 2020 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 






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AMENDMENT 3: 2020 
Amendment 3 is a substantial change to address the addition of a key secondary objective at the surrogate endpoint analysis. Some metabolic endpoints 
(triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c [in diabetic patients], HOMA-IR [in non-diabetic patients]) are upgraded as key 
secondary endpoints that results in addition of a gatekeeping procedure to control the overall type I error rate at a two-sided alpha level of 0.01.  
Furthermore, to be consistent with the Statistical Analysis Plan (SAP), some updates and clarifications are made in the “Statistical Methods and Data Analysis” 
section.  
Other updates to clarify the FibroScan assessments and the rules of discontinuation related to the liver function monitoring were added. The summary of the 
safety data was also updated to reflect the update of the effective Investigator’s Brochure with no changes to the benefit/risk assessment to the medicinal 
product. 
Added text is bolded; deleted text is struck through. 
Summary of major changes to the protocol: 
Section 
New Text 
Section 2 
2 TRIAL OBJECTIVES 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
Section 2.2 
2.2 KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on the following 
endpoint: 
•
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring.
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
•
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c
(in diabetic patients), HOMA-IR (in non-diabetic patients)


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Section 2.3 
2.3 OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 point 
improvement in hepatic ballooning  


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Section 
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o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, hepatic 
ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess histological changes after 72 weeks of treatment and follow up biopsy on the following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow up biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN scoring: total 
NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis activity fibrosis (SAF) activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity 
score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 


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Section 
New Text 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
o 
To assess the onset to:histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
Section 2.5 
2.5 EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION (WHATEVER THE FIBROSIS 
STAGE – F1, F2 OR F3) 
• 
To explore the following endpoints , in F1 patients and in the overall population whatever the fibrosis stage 
(F1, F2 or F3), the same endpoints as for the primary and secondary objectives.exploratory group at Week 
72 and at the end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, lobular inflammation, 
or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), steatosis, hepatic 
ballooning, lobular inflammation, portal inflammation, and SAF activity score. 


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Section 
New Text 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF 36 questionnaire) 
• 
To assess the tolerability and safety. 
Section 9.2.1 
9.2.1 Surrogate endpoint – resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 72 weeks of treatment. 
Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) and disappearance or persistence of minimal 
lobular inflammation (i.e., grade 0 or 1) with an overall pattern of injury not qualifying for steatohepatitis. Worsening of 
fibrosis is evaluated using NASH CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate 
endpoint will be formally assessed at the time of the surrogate efficacy analysis when at least the first 1023 of 
therandomized F2 toand F3 patients complete the 72 week treatment period or discontinue early from the study 
treatment (see Section 9.8.1 for details). An additional exploratory analysis of this endpoint will take place at the time of 
the final analysis. 


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Section 
New Text 
Section 9.2.3 
9.2.3 Key Secondary Endpoints 
The key secondary endpoint isendpoints are: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 weeks. 
ThisTo assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL 
cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
These key secondary endpoints will be assessed at the time of the surrogate endpoint analysis (at least the first 1023 
randomized patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening of fibrosis endpoint. 
Section 9.2.4 
9.2.4 Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow up biopsyat the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow up biopsyat the end 
of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring (at 
the end of LTTP) 
o 
percentage of patients with at least 1 point improvement in of fibrosis of at least 1 stage according to 
NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 


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Section 
New Text 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN scoring: 
total NAS, [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in SAFdisease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
mean percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, hepatic 
ballooning, lobular inflammation, portal inflammation, and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 


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Section 
New Text 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
Section 9.3 
9.3 Analysis Sets 
The following analysis sets will be used in this study: 
•Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
•ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main analysis of the primary 
and key secondary endpoints will be based on the ITT. 
•Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This set will be used to 
summarize safety. 
•Efficacy evaluable set (EES): All F2 and F3 patients in the ITT population who have taken at least one 
dose of study treatment and have a reliable liver biopsy at both baseline and at the end of the 72 week 
treatment period. 
•Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not have any important 
protocol deviations leading to exclusion from the PPS. Important protocol deviations will be defined in the SAP and 
agreed prior to database lock. Supportive analysis of the primary and key secondary endpoints will be based on the 
PPS.  


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•Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
•Full Intent-To-Treat Set (FITT): all randomized patients.  
•Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
Patients in the ITT, FITT, EES, PPS, and exploratory F1 cohorts (study population and efficacy data) will be analyzed based 
on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) will be analyzed based on actual 
treatment received. 
Section 9.4.1 
9.4.1 Resolution of NASH 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of the 72 week 
treatment period will be summarized by treatment group. The main analysis will be performed using a logistic regression 
model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, female), fibrosis stage (F2, F3) and baseline 
NAS. The According to the method described in Ge et al. (2011), the statistical model will be used to 
calculateestimate the odds ratiodifference (elafibranor/placebo) in rate of resolution of NASH without worsening 
of fibrosis and its 99% confidence interval.CI. The main confirmatory analysis will be performed when at least the first 
1023 randomized F2/F3 patients have completed the 72 week treatment period or discontinued from the study treatment. 
The main analysis will be based on the ITT. Supportive analysis will be based on the EES and PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a nonresponder for the 
main analysis. Additional sensitivity analysisSupplementary analyses using multiple imputations and a pattern mixture 
model will be performed, as well as sensitivity analysis using a Cochran-Mantel-Haenszel test. Further details will 
be provided in the SAP. 


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Section 9.5.1 
9.5.1 Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at the end of the 72 
week treatment period will be summarized separately by treatment group. The data will be analyzed using a logistic 
regression model, with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage and baseline NAS by NASH CRN 
scoring. The analysis will be performed at the time of the surrogate endpoint analysis when at least the first 1023 
ofrandomized patients with fibrosis stage F2 and F3 have completed the 72 week treatment period or discontinued from 
the study treatment. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant. A gatekeeping procedure will be constructed to control the overall Type I error rate for testing 
the key secondary efficacy endpoints at an overall two-sided alpha level of 0.01.  
The main analysis will be based on the IIT. Supportive analyses will be based on the EES and PPS. 
Section 9.5.2 
9.5.2 Other secondary endpoints 
Time to event endpoints such as time to first cardiovascular event/death will be analyzed using the Cox proportional 
hazard’s model in the same manner as time to clinical event/death.  
Continuous endpoints will be analyzed using an repeated measures Analysis of Covariance (ANCOVA) model with fixed 
terms for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS, and time-point and treatment by time-
point interaction. An unstructured compound symmetry covariance matrix will be used for this analysis. The statistical 
model will be used to calculate the mean treatment difference and 95% confidence interval. If the data does not meet the 
required assumptions for parametric tests, the data will be analyzed using a nonparametric analysis of covariance method 
of Zink and Koch41. 


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Section 9.5.3 
9.5.3 Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, including, but not 
limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
• 
PNPLA3 (absence or presence of risk allele G [i.e. CC vs GG/CG], and within the at risk group, 
homozygous vs. heterozygous for the risk allel G [i.e. CG vs GG]) 
• 
Patients under statins (yes/no), defined as patients who have duration of IP exposure greater or equal 
to 60 days, with extent of exposure to statin greater than or equal to 30 days before the visit 7 biopsy 
date.  
Section 9.6 
9.6 STRATEGIES TO CONTROL TYPE I ERROR 
A hierarchical gate keeping strategy will be used to control for multiplicity for the The key secondary endpoint. If the 
resolution of NASH without worsening of fibrosisefficacy endpoints will be tested only if the primary surrogate 
endpoint is statistically significant, at a two-sided 1% significance level. A gatekeeping procedure will be 
constructed to control the overall Type I error rate for testing the key secondary endpoint, improvementefficacy 
endpoints at an overall two-sided alpha level of fibrosis according to NASH CRN scoring,0.01. 


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The gatekeeping procedure will be tdestailed in a confirmatory mannerthe SAP and set up using the general 
method for building multi-stage parallel gatekeeping procedures in multiplicity problems with a two sided 
α=0.01.several families of null hypotheses (Dmitrienko and Tamhane, 2011, 2013). 
Section 9.7.2 
9.7.2 Time to clinical event/death 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver fibrosis. In the 72-week 
FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an approximate annual drop-out rate of 4%. Based 
on these assumptions, 456 events are required to provide 80% power to show that elafibranor is superior to placebo with 
respect to time to clinical event/death. In order to obtain 456 events, at least 2022 patients will be required in the IIT. 
The number of patients to be enrolled may be adjusted during the course of the study in a blinded manner to 
achieve the desired number of primary events.  This will be accomplished using standard event forecasting 
methods (Anisimov, 2011). 
Section 9.8.1 
9.8.1 Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when at least the first 1023 randomized F2 and 
F3 patients complete 72 weeks of treatment or discontinue early from the study treatment. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or conditional 
approval submission. This analysis will be done by an unblinded team separate from the study team; the study team will not 
be unblinded until the final analysis at the end of follow-up. A Data integrity plan will be set-up to detail the blinding 
process and address how data will be published in view of marketing authorization and how integrity of the 
trial will be protected. 


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The DSMB will also periodically review safety data from the study to ensure the well-being of study participants. These safety 
reviews will be based on reports generated by the SAC and may One dedicated meeting will be held upon availability 
of the surrogate endpoint analysis results and DSMB will be provided with data summaries that will include 
selected efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not considered 
a formal interim analysis, and no type I error adjustments will be done for these reviews. Details will be in the DSMB Charter. 
 
 
Summary of minor changes to the protocol: 
The following minor changes were made to the protocol. The changes do not impact the reliability of the data generated in the clinical trial or the safety or rights 
of the subjects: 
- 
Study contact details have been updated for one of the Steering Committee members, for the sponsor representative, and several vendors representatives 
- 
The version number and date were updated throughout the protocol 
- 
The list of abbreviations has been updated 
- 
Sections "Number of estimated randomized F2-F3 Patients" and "Study Duration (planned)" of the synopsis were updated. Appropriate sections of the core 
protocol were also updated to reflect the changes. 
- 
The “Section 1.5 - Clinical Studies” was updated to issue synthetic Clinical Studies summaries reflecting the updates of the effective version of the Investigator’s 
Brochure. 
- 
The "Section 1.6 - Conclusion " was updated to reflect the updates of the effective version of the Investigator’s Brochure. 
- 
The “Section 6.2.5 - Fibroscan” was clarified for the assessment conditions. 
- 
The “Section 6.3.2.1 - Monitoring of patients with normal baseline aminotransferase values” and the “Section 6.3.2.2 - Monitoring of patients with increased 
baseline aminotransferase values” were updated to clarify the conditions of the associated parameters “INR” and “eosinophilia”. 
- 
The "Section 6.3.3 - Threshold for diagnosis of cirrhosis" was updated for liver biopsy consideration 


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- 
The “Section 6.6 - Guidances for Investigators” was updated to reflect the updates of the effective version of the Investigator’s Brochure. 
- 
The section 7.4 has been very slightly clarified 
- 
The section 9.5.4 has been updated to include the FITT 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with 
fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on 
the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by 
a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, all-cause mortality, and 
liver-related clinical outcomes as measured by the onset of any of the listed adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
 
Primary objective – surrogate endpoint analysis  
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
Hepatocellular carcinoma 
• 
the onset of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objectives (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c 
(in diabetic patients), HOMA-IR (in non-diabetic patients) 
 
 
Other secondary objectives 
• To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH 
CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), 
or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 
point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire) 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory objectives 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
 
Exploratory objectives for F1 group and the overall population (whatever the fibrosis stage – F1, F2 or F3) 


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• 
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or F3), 
the same endpoints as for the primary and secondary objectives 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver markers 
o 
renal biomarkers (including urinalysis) 
o 
cardiac biomarkers 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening Period) 
with: 
• 
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine aminotransferase 
(ALT; absence of normal value of ALT within the past year), obesity defined by a body mass index 
(BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or homeostasis model 
assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement for 
presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is confirmed 
as well as any other event listed in the long-term composite endpoint, patients will be discontinued from 
study. 
Number of estimated randomized F2-F3 Patients: at least 2022 patients (ratio 2:1) 
• 
674 patients in placebo group  
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~270 centers 
Number of participating countries: 24 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, Mexico, 
Colombia, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 96 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week -12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or placebo 
for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  


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o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented 
ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the patient)  
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at least 
1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 
in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  
o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy within 
6 months before Screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation). 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic 
drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-
1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months prior 
to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose in the 
6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until 
the end of treatment. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c 
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal 
HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or 
positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease  
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
 
Concomitant medications: 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or other nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 
19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
24. Positive anti-human immunodeficiency virus antibody. 
25. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients are 
allowed into the study. 
27. International normalized ratio >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 


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29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). 
31. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 96 months after the first patient is randomized. 
 
Key secondary endpoints (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 
weeks. 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
 
Other secondary endpoints  
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 


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o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – Sep 2018 
• 
Recruitment period: March 2016 – May 2020 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q1 2020 – Q2 2020 
• 
LPLV (LTTP): estimated within Q1 2024 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a safety 
data review on a regular basis during the trial to protect patient welfare and preserve study integrity. The 
DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist all of whom will be 
independent of the participants in the study. 
 








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- 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the patients 
5. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to Randomization 
Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact requires 
a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having permanently 
discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. In the LTTP the first ECG will be performed at V9 and then every 48. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively), 
and every 48 weeks thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 
 








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5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic and 
biomarker ICF. 
6. 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1) are 
available, then SV1 and V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits should 
be scheduled in order to obtain the needed results prior to the randomization. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
AMENDMENT 3: 2019 ......................................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 23 
TABLE OF CONTENTS ....................................................................................................................... 40 
TABLE OF TABLES ............................................................................................................................ 46 
TABLE OF FIGURES .......................................................................................................................... 47 
LIST OF ABBREVIATIONS .................................................................................................................. 48 
1.
INTRODUCTION ................................................................................................................. 51 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 51 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 51 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 53 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 54 
1.4.1. 
Pharmacology .......................................................................................................... 54 
1.4.2. 
Safety pharmacology ................................................................................................ 54 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 54 
1.4.4. 
Toxicology ............................................................................................................... 55 
1.5. 
CLINICAL STUDIES ............................................................................................................. 56 
1.5.1. 
NASH ...................................................................................................................... 56 
1.5.2. 
PBC ........................................................................................................................ 57 
1.6. 
CONCLUSION ..................................................................................................................... 58 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 58 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 59 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 59 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 59 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) ............................... 60 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 60 
1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 61 
2.
TRIAL OBJECTIVES ............................................................................................................. 63 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 63 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 63 


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2.1.2. 
Long-term endpoint ................................................................................................. 63 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS .................................. 63 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 64 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 65 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION (WHATEVER THE 
FIBROSIS STAGE – F1, F2 OR F3) ........................................................................................ 65 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 65 
3. 
TRIAL DESIGN .................................................................................................................... 66 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 66 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 66 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 67 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 67 
3.5. 
STUDY PERIODS ................................................................................................................. 67 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) ...................................................................... 67 
3.6.1. 
Screening visits SV1 and SV2 .................................................................................... 67 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): ....... 69 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 69 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 69 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 70 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 70 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 71 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 72 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 72 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 73 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 74 
3.11. OPTIONAL VISITS .............................................................................................................. 75 
3.11.1. 
Retesting screening visits .......................................................................................... 75 
3.11.2. 
Unscheduled visits ................................................................................................... 75 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY ................................................................................. 75 
4. 
PATIENT SELECTION .......................................................................................................... 76 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 76 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 77 
5. 
TRIAL PROCEDURES ........................................................................................................... 80 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 80 
5.1.1. 
Standard diet and exercise recommendations ............................................................. 80 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 80 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 81 
5.1.4. 
Sun exposure .......................................................................................................... 81 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 81 


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5.2.1. 
Handling of patient withdrawal .................................................................................. 81 
5.2.2. 
Permanent discontinuations of study drug .................................................................. 81 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 82 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 83 
5.2.5. 
Replacement ........................................................................................................... 83 
5.2.6. 
Premature discontinuation of the study ...................................................................... 83 
5.3. 
PATIENT RESCREENING ...................................................................................................... 83 
6. 
ASSESSMENTS ................................................................................................................... 85 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 85 
6.1.1. 
Histological assessments ........................................................................................... 85 
6.1.2. 
Biological assessments ............................................................................................. 86 
6.1.3. 
Constitution of biobank ............................................................................................. 87 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 88 
6.2.1. 
Physical examination ................................................................................................ 88 
6.2.2. 
Waist circumference ................................................................................................. 88 
6.2.3. 
Vital signs ............................................................................................................... 88 
6.2.4. 
Electrocardiogram .................................................................................................... 89 
6.2.5. 
FibroScan ................................................................................................................ 89 
6.2.6. 
Quality of life questionnaire ...................................................................................... 89 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 89 
6.3.1. 
Creatine phosphokinase ............................................................................................ 89 
6.3.2. 
Liver function monitoring .......................................................................................... 90 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 91 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 92 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 92 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 92 
6.6.1. 
Summary of safety data............................................................................................ 92 
6.6.2. 
Safety data conclusion .............................................................................................. 95 
6.6.3. 
Benefit/risk assessment ............................................................................................ 95 
7. 
TREATMENTS ..................................................................................................................... 97 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS .............................................................................. 97 
7.2. 
PACKAGING AND LABELING ................................................................................................ 97 
7.2.1. 
Packaging ............................................................................................................... 97 
7.2.2. 
Labeling .................................................................................................................. 97 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ......................................... 98 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 98 
7.5. 
STORAGE CONDITIONS ...................................................................................................... 98 
7.6. 
DISPENSING OF TREATMENT .............................................................................................. 98 


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7.7. 
TREATMENT REPLACEMENT ................................................................................................ 99 
7.8. 
PROCEDURE FOR BLINDING ................................................................................................ 99 
7.9. 
PROCEDURE FOR UNBLINDING ........................................................................................... 99 
7.10. STUDY DRUG COMPLIANCE ............................................................................................... 100 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................ 100 
7.12. OTHER MEDICATION ........................................................................................................ 100 
7.12.1. 
Handling of concomitant medication ........................................................................ 100 
7.12.2. 
Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) ........................................................................................................... 101 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) ...................................................................... 101 
7.12.4. 
Permitted medication ............................................................................................. 102 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................. 103 
8.1. 
DEFINITIONS ................................................................................................................... 103 
8.1.1. 
Adverse events ...................................................................................................... 103 
8.1.2. 
Serious adverse events ........................................................................................... 104 
8.1.3. 
Clarification on serious adverse events: .................................................................... 105 
8.1.4. 
Adverse drug reaction ............................................................................................ 106 
8.1.5. 
Unexpected adverse event ...................................................................................... 106 
8.2. 
ASSESSMENTS ................................................................................................................. 106 
8.2.1. 
Intensity assessment .............................................................................................. 106 
8.2.2. 
Relation to the study treatment ............................................................................... 107 
8.2.3. 
Action taken and outcome ...................................................................................... 107 
8.3. 
REPORTING ..................................................................................................................... 108 
8.3.1. 
Reporting an adverse event .................................................................................... 108 
8.3.2. 
Reporting a serious adverse event ........................................................................... 108 
8.3.3. 
Follow-up .............................................................................................................. 110 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 110 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 110 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 110 
8.6.1. 
Pregnancy ............................................................................................................. 111 
8.6.2. 
Medication error..................................................................................................... 111 
8.6.3. 
Misuse .................................................................................................................. 111 
8.6.4. 
Overdose .............................................................................................................. 111 
8.6.5. 
Abuse ................................................................................................................... 112 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 113 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 113 
9.2. 
ENDPOINTS ..................................................................................................................... 113 


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9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 113 
9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 113 
9.2.3. 
Key Secondary Endpoints ........................................................................................ 114 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 114 
9.2.5. 
Exploratory endpoints ............................................................................................. 116 
9.3. 
ANALYSIS SETS ................................................................................................................ 116 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 116 
9.4.1. 
Resolution of NASH ................................................................................................ 116 
9.4.2. 
Long-term endpoints .............................................................................................. 117 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 118 
9.5.1. 
Key secondary endpoint.......................................................................................... 118 
9.5.2. 
Other secondary endpoints ..................................................................................... 118 
9.5.3. 
Subgroup analyses ................................................................................................. 118 
9.5.4. 
Exploratory analyses .............................................................................................. 119 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 119 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 120 
9.7.1. 
Resolution of NASH ................................................................................................ 120 
9.7.2. 
Time to clinical event/death .................................................................................... 120 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 121 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 122 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 122 
10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 123 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 123 
10.2. RETENTION OF RECORDS ................................................................................................. 123 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 125 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 125 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 126 
11.3. QUALITY ASSURANCE ....................................................................................................... 126 
12. 
ETHICS AND REGULATORY................................................................................................ 127 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 127 
12.2. COMPETENT AUTHORITY .................................................................................................. 128 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 128 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 128 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 129 
13. 
FINANCING AND INSURANCE ............................................................................................ 130 
13.1. FINANCIAL ISSUES ........................................................................................................... 130 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 130 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 131 
14.1. STUDY REPORT ................................................................................................................ 131 


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14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 131 
15. 
REFERENCES LIST ............................................................................................................ 133 
APPENDICES .................................................................................................................................. 136 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 137 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 145 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 146 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 148 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 149 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
30 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
34 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
94 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
38 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
39 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 


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GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IQR 
InterQuartile Range 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFL 
 
nonalcoholic fatty liver  
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PBC 
Primary Biliary Cholangitis 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis-activity- fibrosis 
SAP 
Statistical Analysis Plan 


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SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
UDCA 
UrsoDeoxyCholic Acid 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD where 
steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) and 
the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue owing 
to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high prevalence 
of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in Europe and 
27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance spectroscopy, 
34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte FFA 
load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver (second 
hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor cells and 
associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse range and 
high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate cells (HSC) 


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and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic factors that 
recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to fibrogenesis. 
Collagen and other extracellular matrix components accumulate within the liver, which may result in 
distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can be 
considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in disease 
progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing injurious 
and fibrotic mechanisms resulting in disease progression, it should not be considered a sole therapeutic 
target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the “second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been associated 
with a reduction in generation of reactive oxygen species and Kupffer cell activation, which might attenuate 
injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin contributes to an 
insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells are 
the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the proapoptotic 
gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, caspase levels, by-
products of cellular apoptosis, are also increased in these groups of patients. 


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1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the fibrate 
class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis and 
upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in serum 
triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in cholesterol 
efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and C-reactive 
protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with fibrates 
in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with clofibrate 
in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or triglycerides 
levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via improved 
insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory responses, 
and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the potential to 
target multiple components of the metabolic syndrome, including obesity, dyslipidemia, hypertriglyceridemia 
insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice compared 
to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak inducer of 
apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ as 
a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin sensitivity, 
and suppresses inflammation. The finding raise the possibility that small molecule agonist of PPARδ may be 
effective therapeutic targets for the treatment of chronic inflammation in the liver.  


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The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, in 
several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with elafibranor 
confers liver protection both in preventive and therapeutic approaches on established pathologies. These 
effects have been demonstrated through plasma and hepatic markers, as well as liver macro- and micro- 
histological examination. These studies have shown that elafibranor acts on several mechanisms involved in 
NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have 
demonstrated that both PPARα-dependent and PPARα-independent mechanisms participate in the beneficial 
effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
 Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor has 
insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic treatment 
of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic plaques in 
the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was moderate 
(about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by the active 
metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both elafibranor and 
GFT1007 linearly increase with the dose after single or repeated administrations. Elafibranor and its 
metabolites are rapidly cleared from the plasma and they are totally excreted by both fecal and renal route 
within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into the bile and undergo 


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an extensive entero-hepatic cycle giving support for liver targeting of elafibranor and/or GFT1007. The 
distribution study in the rat supports the liver targeting of elafibranor and/or its metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. Thus, 
the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug metabolism 
should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed through a clinical 
study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of elafibranor 120 mg 
administered for 14 days alone or with a single administration of warfarin. This study demonstrated that 
elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal metabolite 
GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the potential for 
drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, elafibranor 
(GFT505) has recently been assessed in a follow-up clinical DDI study with the OATP1B3-sensitive substrate, 
atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no evidence 
of the formation of unique human metabolites or metabolites formed at disproportionately higher levels in 
human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 


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1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose oral 
administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year repeated-dose 
carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated hepatomegaly, 
hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). However, it is well known 
that, compared to nonhuman primates and humans, rodents are highly sensitive to PPARα agonist induced 
peroxisome proliferation and associated liver side effects. Thus, available information on this class of drug 
which includes marketed fibrates together with the lack of any liver side effects in monkeys treated with high 
doses of elafibranor for 1 year support the nonrelevance to human.19 Overall, these studies did not reveal 
any other safety issues up to the highest doses tested. Notably, elafibranor did not have any of the known 
PPARγ-related concerns such as excess in weight gain, hemodilution, edema, cardiomegaly, adiponectin 
induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and the 
UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect level 
(NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered that data 
are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor (GFT505), 
and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
NASH 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 completed clinical trials, and 5 still ongoing. A total of 561 healthy lean subjects, 
60 overweight or obese subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 
20 with hepatic impairment (Child-Pugh class A, B or C) have been randomized to date in the completed 
trials. Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 


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A Phase 2 program was initiated to assess the safety and efficacy profile of elafibranor in subjects with 
cardiometabolic disorders and NASH. To date, 5 Phase 2a studies have been completed, in which 297 
subjects were randomized: 37 with mixed hyperlipidemia (type IIb Frederickson); 94 with atherogenic 
dyslipidemia and abdominal obesity; 47 with impaired glucose tolerance and abdominal obesity; 97 with 
diabetes mellitus type II; and 22 with insulin resistance and abdominal obesity. A Phase 2b study has also 
been completed, in which 274 subjects with NASH were randomized. In the Phase 2 program, the elafibranor 
daily doses ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months.  
A Phase 2a randomized, open-label, sequential cohort study (GFT505E-218-1) will assess the PK and 
pharmacodynamic (PD) profile and the safety and tolerability of two dose levels of GFT505 (80 mg and 120 
mg) in children and adolescents, 8 to 17 years of age, with NASH. In this study, subjects will receive 80 or 
120 mg of GFT505 once daily for 12 weeks. The study consists of two paediatric patient cohorts with NASH 
which will be dosed sequentially. Cohort 1 will consist of +/- 12 subjects who are ≥12 to ≤17 years of age. 
Once 10 subjects in cohort 1 have been evaluated for PK and safety through Visit 4 (30 days) by an 
independent Data Safety Monitoring Board (DSMB), enrollment will be open to subjects ≥8 to ≤11 years of 
age. Cohort 2 will consist of +/- 8 subjects who are ≥8 to ≤11 years of age.  
At time of DSUR data lock point (31 July 2019), 1 subject (≥12 to ≤17 years of age) had been enrolled and 
exposed to at least one administration of GFT505. 
A Phase 2 study (GFT505-219-8) to evaluate the effect of a 6-week elafibranor (120 mg) treatment 
administered once daily on hepatic lipid composition in subjects with nonalcoholic fatty liver (NAFL) is 
currently ongoing. This study intends to achieve mechanistic information about the mode of action of 
elafibranor on the (lipid) metabolism in the human fatty liver. Subjects with NAFL will receive 120 mg of 
GFT505 or placebo once daily for 6 weeks in randomized order in a crossover design. Overall, 16 subjects 
with NAFL are intended to be included. 
For additional information see Investigator’s Brochure. 
1.5.2. 
PBC 
Based on the mechanism of action of elafibranor, and on the relevant efficacy and safety data collected to 
date, specifically on decrease in ALP and inflammation markers, a Phase 2a study has been launched in PBC 
has been completed, under IND 132202, filed in September 2016. The aim of this study was to validate the 
efficacy of elafibranor on ALP decrease in this patient population, and to confirm its safety in a population 
with PBC. This study was designed to compare the effect of daily oral administration for 12 weeks of GFT505 
80 mg and 120 mg on changes in serum alkaline phosphatase (ALP) to that of placebo in subjects with PBC 
and inadequate response to ursodeoxycholic acid (UDCA). 
For additional information see Investigator’s Brochure. 


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1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers.  
Moreover at the last DSUR cut-off date (31 July 2019), 25 clinical studies with elafibranor have been 
conducted or are ongoing (in which a total of 3245 subjects have been randomized, including an estimated 
2206 subjects exposed to elafibranor. In general, the treatment was well tolerated. No interaction, 
medication errors, or abuse/misuse cases have been reported to this date. See Section 6.6 for further 
information. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can progress 
to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with mild to 
moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a reasonable 
timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the evaluation 
of long-term outcomes including progression to cirrhosis should ensure that an expected number of events, 
calculated based on progression rate for each fibrosis stage, are obtained. Based on the literature,21,22,23,24,25 
in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be estimated at 8% per year 
for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. Generally, 
liver decompensation events occur only when cirrhosis is present and the progression rate to the other events 
is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk of 
fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the Phase 
I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In this model, 
the studied response was the change at endpoint versus baseline in biochemical parameters known to be 
associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes (ALT, GGT, alkaline 
phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based on this modeling, the 
optimum dose was consistently assessed as a value of 118 mg. Therefore, given its good safety profile and 
evidence of efficacy, both supported by the dose-response modeling, 120 mg elafibranor appears to be the 
most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 i.e., 
reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with increased 
hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies are now 
available showing that patients with steatohepatitis but not those with steatosis only (i.e., nonNASH NAFLD) 
are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis for "resolution of 
NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced by the academic 
community and expressed in several scientific society endorsed position papers.29,30 Based on the recently 
published recommendations from this workshop,30 resolution of NASH with no worsening of fibrosis may be 
an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and fibrosis. Based 


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on recent data that have shown that fibrosis stage of 2 or more is related to liver-related mortality,22 the “no 
worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint).  
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score ≥15, 
hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, variceal 
bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, hepatopulmonary 
syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy [provided that 
these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most accurate 
estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 2145.5 person-
years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an 
improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a population of patients with 
NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 0.14 stage/year in a population 
of patients with NASH. In another study of 108 patients, no significant difference in the proportion exhibiting 
fibrosis progression was found between those with NAFLD or NASH.31 In the whole cohort, the mean annual 
rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths between 
treatment and control groups can be considered as a potential clinically meaningful outcome measure for 
clinical trials. This long-term outcome including progression to cirrhosis is considered acceptable,30 and 
required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH without 
worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  


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1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the chronic 
toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of elafibranor does 
not reveal any major safety concern, based on the conclusion that elafibranor-induced liver toxicity in rodents 
is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year but improvement of liver 
function markers) and humans (consistent improvement of liver function markers in all Phase II trials). These 
toxicology results and conclusions are on-line with the extensive literature on the liver effects of PPAR 
agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine ratio, 
cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, kidney 
injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived estimated 
glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each visit, as well 
as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and will be reviewed 
on an ongoing basis through regular safety reviews by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the DSMB. 
In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored throughout the 
study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 


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For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 


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• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to SAF scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 


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o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION 
(WHATEVER THE FIBROSIS STAGE – F1, F2 OR F3) 
• 
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or F3), 
the same endpoints as for the primary and secondary objectives. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize at least 2022 F2/F3 patients to either active (1348 patients) or placebo 
(674 patients) treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 
enrolled patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 
at least 2 of the following conditions: persistent elevated (absence of normal ALT within the past year, 
obesity defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education 
Program’s Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also 
be enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of at least 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 


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• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 96 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be redefined 
according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory part of the 
study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an 
event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) 
3.6.1. 
Screening visits SV1 and SV2  
The following screening procedures will be performed for all potential patients at SV1 conducted during the 
screening period and prior to randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 
• 
Physical examination (described in Section 6.2.1). 


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• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in Section 7.12 
and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an additional 
SV2 visit at least Week -4 prior to the planned Randomization V1, in order to obtain the results in time. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 
months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart in 
order to have 2 consecutive values for DILI adjudication.   
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 30, and 31 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 
 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended 
Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an additional 
SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood samples 
for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver biopsy. 
Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results from 
the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call within 
1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon 
as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the 
Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 3, 
ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant cardiometabolic 
comorbidities, which are associated with rapid progression of the disease (listed in Section 3.1), will also be 
enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under treatment 
in order to evaluate the effect of elafibranor on the liver histology. 
When at least the first 1023 randomized patients (F2-F3) complete Week 72 (or discontinue early from the 
study treatment), a surrogate endpoint analysis will be performed and potentially filed for initial market 
approval under Subpart H or conditional approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in the 
permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 


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• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX III: Permitted/non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous 
visit (for WOCBP only, every visit from V1)   
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.5) 
• 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described in 
Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, death 
due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  described 
in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of the study 
following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 


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3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 1 week 
before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX III: Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous 
visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and tested 
at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP compliance 
control. If any information during this phone contact requires a visit, the Investigator may decide to perform 
an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed for each phone visit. 


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3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop treatment 
and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after the 
final administration of study drug. Patients who permanently discontinue study drug for any reason other 
than an event listed in the primary composite endpoint for long-term efficacy described in Section 1.9.2 will 
remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy outcomes 
and safety through phone call visits every 24 weeks as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the site 
and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT Visit 
see Table 1, Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return (if 
required). The following procedures will be performed at the EOT Visit: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in
Section 5.1.2), and tobacco habits
•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX III: Permitted/non-permitted medication) 
•
Quality of life assessment (described in Section 6.2.6)
•
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8)
•
Blood samples (described in Table 2)
•
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed)
•
Urinalysis and urinary dipstick (described in Table 2),
•
Urinary pregnancy test (for WOCBP only)
•
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only)
•
Record waist circumference
•
12-lead ECG (described in Section 6.2.4)
•
Drug accountability.
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 


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3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
the onset of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
 ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 


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 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided 
that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional testing 
is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to Randomization 
(V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for safety 
reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding capability. 
Specific study documents will be prepared and Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as described 
below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning with 
a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal ALT 
within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III definition), 
type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or UDCA; a stable dose from at least 6 months prior to diagnostic liver biopsy is 
required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic 
drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months 
prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the 
course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept constant 
for at least 2 months prior to Screening. 
19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 


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(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
24. Positive anti-human immunodeficiency virus (HIV) antibody. 
25. AST and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
27. INR >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 
29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with 
markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
31. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for each 
patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 7 days. 
• 
On each study visit day, study treatment will be taken under fasting conditions after the blood 
sampling (which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. Alcohol 
consumption of more than 20 g per day for women and 30 g per day for men is considered abusive 


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(see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams (0.6 ounces) 
of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be 
discussed 
with 
the 
Investigator 
before 
doing 
so 
(see 
Section 
7.12 
and 
APPENDIX III: Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1). 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be permanently 
discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the Medical 
Monitor informed. If the discontinuation of study drug is due to an AE, the event should be documented in 
the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 


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•
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2)
•
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision
•
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of background 
therapy that may put the patient at risk with continued participation
•
Non-permitted 
concomitant 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX III: Permitted/non-permitted medication)
•
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to
use a reliable method of birth control during the study will be permanently discontinued from study
drug
•
Non-compliance with the study treatment
•
Uncooperative patient
•
The patient requests to stop study drug permanently.
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever is 
sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible with 
this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 


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period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and 
is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to contact 
patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the site. Vital 
status will be collected within legal and ethical boundaries for all patients randomized, including those who 
did not get study drug. Vital status will be searched in public sources during the study close-out period. If 
vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of patients, 
but intends only to exercise this right for valid scientific or administrative reasons. After such a decision, the 
Investigator must contact all participating patients within a reasonable period of time. As directed by the 
Sponsor, all trial materials must be collected and all eCRFs completed to the greatest extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. Prompt 
compliance with this requirement is essential so that the Sponsor may comply with its regulatory obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 


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the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, and 
the risks to the patient should not outweigh the potential benefits. This will be assessed by the investigator 
according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in liver 
disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe biopsy 
should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies to 
determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. Biopsy 
slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site.  
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Liverpat, 28 rue de l’amiral Hamelin, 75 116 Paris– 
France) where they will be read and scored. Scores for total NAS, steatosis, ballooning, lobular inflammation, 
or portal inflammation, as well as fibrosis scores (both by NASH CRN scoring system, and NAFLD Ishak 
scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- Loos, 
France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 24 hours 
after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, signed, 
and dated by the Investigator as soon as they are received. The Investigator should comment upon out of 
range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 3.11. 
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the site 
within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3).  
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, at 
each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time of 
the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale for 
weight must be the same for a given patient throughout the visits. 
6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in cm 
during expiration. The measuring tape should be snug but not compressing the skin and held parallel to the 
floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the exception 
of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement in Humans 
and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated manometer 
should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the LTTP. 
Where possible, FibroScan must be done at the day of visit. Otherwise, it can be performed within 7 days 
around the visit date.  
Recommendations for ensuring a reliable examination are:  
• 
Patient must be fasting for at least 2 hours before the FibroScan examination 
• 
At least 10 consecutive and successful measurements shall be performed without changing probe 
position 
• 
InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, 
to consider a FibroScan measure as reliable. If not, it is recommended to perform a few additional 
individual measures, or to restart the entire FibroScan examination 
 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, V3, 
V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP until, 
and including the EOT visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, and/or 
marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 3 to 7 
days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle tenderness 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be considered and 


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the patient must be discontinued from study treatment immediately and followed up as described in 
Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, the 
CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN.  
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned randomization 
visit (V1), or, using lab results from SV1 and V1 that are at least 8 weeks apart.  
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once a 
week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin >2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 


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•
Increase in AT >3 x ULN AND increase in INR>1.5 (except in case of anticoagulant therapy):
permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and
Section 5.2.2).
•
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness,
fever, rash: permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9
and Section 5.2.2).
•
Increase in AT >3 x ULN AND eosinophilia (>5%) with total count > ULN: permanently discontinue
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any visit 
post V1 onwards during the treatment periods exhibit: 
•
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per
assessment schedule
•
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours
o
AT remains >3 x baseline value but ≤10 x ULN: continue the drug with close serial
monitoring (once a week)
o
AT increases >5 x baseline value or >10 x ULN: permanently discontinue patient from study
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently discontinue
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x baseline value AND increase in INR>1.5 (except in case of anticoagulant
therapy): permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9
and Section 5.2.2).
•
Increase in AT >3 x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT Visit
(see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x baseline value AND eosinophilia (>5%) with total count > ULN: permanently
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
A liver biopsy may be considered in order to confirm the diagnosis of cirrhosis if during a LTTP visit the 
FibroScan value is ≥ 14 kPa (with IQR/Median stiffness ratio < 30%*) associated with a platelet count 
<150 000/mm3 and at least 1 elevated serum marker of fibrosis indicative of cirrhosis (calculated NAFLD 
fibrosis >0.676 score or reported FIB-4 >2.67). 


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*InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, to 
consider a FibroScan measure as reliable. If not, it is recommended to perform a few additional individual 
measures, or to restart the entire FibroScan examination.  
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, such 
as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for diagnosis of 
cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will discontinue 
the study drug and the study and will be followed up as described in Section 5.2.2 and Section 5.2.3. 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events. A detailed description of 
the interim analysis procedures and decision-making process will be provided in the DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 
1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the participants in 
the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite efficacy 
long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist, all of whom will be 
independent of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 completed and 5 ongoing clinical trials. A total of 659 volunteers were randomized in 
these studies performed in Phase I centers, including 561 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 20 with hepatic impairment 


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(Child-Pugh class A, B or C) have been randomized to date in the completed trials. Elafibranor daily doses 
ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients suffering 
from cardiometabolic disorders and NASH. To date, 5 Phase IIa studies have been completed in which 297 
patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety of 
elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. A Phase 2 study (GFT505B-
216-1) was also conducted in Primary Biliary Cholangitis (PBC) and included 45 patients with PBC and 
inadequate response to UDCA. This study evaluated the efficacy and safety of elafibranor at doses of 80 mg 
and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor daily doses ranged between 
30 mg and 120 mg, with a maximum treatment duration of 12 months. 
Of the 63 Treatment emergent SAEs that have been reported cumulatively in the completed clinical 
development program, 50 occurred with elafibranor and 13 with placebo. For all SAEs, the treatment code 
has been broken (end of study unblinding). 
Of the 50 SAEs that occurred with elafibranor, only 10 SAEs reported in 7 subjects were considered as having 
a reasonable possibility of relationship to elafibranor by the investigators (serious adverse reaction). They 
consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in 
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
• 
Autoimmune hepatitis in a 56-year-old subject after 12 weeks of treatment of 120 mg elafibranor.  
The subject received her last dose of investigational product before the event.  
For atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease, after later investigations, 
given the medical history of the patients or the time of occurrence of the event, relationship to elafibranor 
was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  


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Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of diarrhea, and vomiting. For general disorders, the main 
symptoms were fatigue / asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
based on creatinine). Myalgia, decrease of appetite dizziness and rash were also reported in more than 1% 
of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical trials, 
given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is monitored in 
clinical trials. For this reason, it is recommended that investigators review these lab results in the course of 
clinical trials. 
System Organ Class 
Adverse Reaction 
Severity 
Number of cases 
(Frequency %) 
Gastrointestinal disorders 
Diarrhea 
Mild to 
moderate 
17 (2.8%) 
Vomiting 
Mild to 
moderate 
9 (1.5%) 
General disorders and administration 
site conditions 
Fatigue / Asthenia 
Mild to 
moderate 
17 (2.8%) 
Investigations 
Hepatic enzymes 
increased (mainly 
transaminases) 
Mild to severe 
13 (2.1%) 
Blood creatine 
phosphokinase increased 
Mild to 
moderate 
6 (1.0%) 
Musculoskeletal and connective tissue 
disorders 
Myalgia 
Mild to severe 
9 (1.5%) 
Metabolism and nutrition disorders 
Decreased appetite 
Mild to severe 
9 (1.5%) 
Nervous system disorders 
Dizziness 
Mild to 
moderate 
6 (1.0%) 
Skin and subcutaneous tissue disorders 
Rash 
Mild to 
moderate 
8 (1.3%) 
Renal and urinary disorders 
Renal failure/impairment 
Mild to 
moderate 
7 (1.1%) 


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Other known effects of PPARα agonists include the increase of creatinine, which was observed in our phase 
IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should also be 
monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014)34.  
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with highly effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol.  
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders and asthenia / fatigue are 
considered common non-serious adverse reactions reasonably associated with elafibranor. Most of them are 
of mild to moderate intensity. Laboratory increases in serum creatinine or CPK should be monitored 
throughout clinical trials as this has been observed in Phase II trials to date, and is a known PPARα agonist 
effect. Elevation of AT will be monitored as well as DILI. In the absence of extensive human pregnancy data, 
highly effective contraception should be maintained for women of childbearing potential participating in 
clinical trials with elafibranor treatment, up to 1 month after end of study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential of 
elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy of 
elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial was 
short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg daily, 
improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg concomitantly 
improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, total and 
LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and glucose 
homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the objective 
to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Furthermore, the Phase IIa trial in PBC subjects who had an inadequate response to UDCA demonstrated 
similar improvement in GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP levels 


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was observed, resulting in significant treatment effects versus placebo on the primary endpoint, whilst also 
meeting the composite endpoint used for drug registration (i.e. serum ALP <1.67 x ULN, an ALP decrease 
>15% and total bilirubin <ULN). 
Moreover, these studies have highlighted the good safety profile of elafibranor and no major safety concerns 
have been raised. 
Despite this favorable benefit-risk profile, an independent DSMB is to be established in order to review the 
safety of the treatment during the trial in an unblinded manner, to protect patient welfare and preserve study 
integrity. The safety assessments will be performed on a regular basis, every 6 months after Randomization 
of the first patient. The DSMB will consist of 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 
hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all independent of the participants in the 
study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil blisters. 
This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use only” 
or other similar/appropriate statements as well as the following instructions “Please return empty packaging 
and unused products to your doctor at your next visit.” Details of carton and wallet labels are detailed in 
APPENDIX V: Product carton and wallet labeling. 
 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before breakfast 
with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages (containing 
96 tablets to last approximately 3 months) allocated to the site. The pharmacy will acknowledge receipt of 
the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when applicable, 
results of any retesting performed), and if the patient fulfills all criteria to enter the treatment period, the 
Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described in 
Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the final database lock and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and ensure 
the study drug is at site for the visits occurring. The IXRS will continue to project study drug requirements 
per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication containing 
the adequate number of wallets to cover the drug administration for the period between visits. The time 
between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment Period and 
24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond to the 
number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be reported 
in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned to active 
treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial medication 
to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of the 
study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or unused) 
and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may destroy 
used and unused study drugs in accordance with the site SOP and always after the drug accountability has 
been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling) 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II, 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 


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within 6 months prior to Screening) and information should be communicated to the Medical Monitor in order 
to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I, 
APPENDIX III: Permitted/non-permitted medication) 
The 
following 
medications 
are 
not 
allowed 
within 
the 
timeframe 
given 
in 
APPENDIX III: Permitted/non-permitted medication): 
• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 weeks 
of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted 
medication 
under 
condition 
(see 
Table 
II, 
APPENDIX III: Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
UDCA. 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an “as-needed” 
basis. Patients should be discouraged from starting any new medication without consulting the Investigator 
unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical 
(investigational) product and which does not necessarily have to have a causal relationship with this 
treatment will be considered as an AE. The term AE is synonymous with the term “adverse experience” as 
used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the Screening 
Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE.  
The questions concerning whether the condition existed before the start of the active phase of the study and 
whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, but 
the severity or frequency increases during the active phase. The active phase of the study begins at the time 
of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of seriousness 
(as defined above) and considered to be possibly related (according to the Investigator) to any study-specific 
procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in the 
hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will not 


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be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social reasons 
will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the protocol. 
Day or night survey visits for biopsy or surgery required by the protocol are not considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the study 
center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement due 
to a pre-existing condition of osteoarthritis of the knee that has not worsened during the study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 


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• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as SAE. 
Hospitalization or prolonged hospitalization for a complication of such procedures should be reported 
as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 


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8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related to 
study treatment. The Investigator will evaluate any changes in laboratory values, make a determination as 
to whether or not the change is clinically important, and whether or not the changes were related to study 
drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or clinically 
significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration and 
it cannot be explained by the patient's clinical state or the study procedures/conditions. The AE 
abates upon discontinuation of the study drug and reappears when the study drug is introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not likely 
because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because information 
is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
• 
Recovered/resolved 


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• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the Screening 
Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s medical record 
from the ICF signature until study end for each patient. Whenever possible, symptoms should be grouped 
as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal intensity, 
action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion as to whether 
there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and which 
is considered by him/her to be caused by the study drug within a reasonable possibility, should be reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that are 
not confirmed by adjudication will be reported as described with the start of the reporting time window being 
the time of negative adjudication decision. 
Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator becoming 
aware of the event). 


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ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail:
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE Form. 
The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment of the 
event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to allow a 
complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 24 hours 
of becoming aware of additional information such as diagnosis, outcome, causality assessment, results of 
specific investigations, and any new significant information that has not been previously reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, autopsy 
reports, and other documents should be sent when requested and applicable. All provided reports must be 
anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the concerned 
Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned according to the 
country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical research 
organization (CRO) may be required to expedite report to the Regulatory Authorities for: 
• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 


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Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information included 
in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the patient 
has left the study and that additional investigations may be requested by the Sponsor. This information 
should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and which 
is considered by him/her to be caused by the study drug within a reasonable possibility, should be reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 
8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or overdose, 
and reports associated with product complaints. 


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8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow reasonable 
attempts to be made to obtain information on any possible medicinal product exposure to an embryo or 
fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be reported 
as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as appropriate 
(see Section 8.3). 
8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or cumulatively, 
which is above the maximum recommended dose according to the authorized product information (see 
Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 


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8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP may 
be revised during the study only to accommodate protocol amendments and to make changes to adapt to 
unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis and 
stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 72 weeks 
of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) and 
disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall pattern of 
injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN fibrosis staging 
system and defined as progression of at least 1 stage. This surrogate endpoint will be formally assessed at 
the time of the surrogate efficacy analysis when at least the first 1023 randomized F2 and F3 patients 
complete the 72 week treatment period or discontinue early from the study treatment (see Section 9.8.1 for 
details). An additional exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 


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• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 96 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoints 
The key secondary endpoints are: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL 
cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
 
These key secondary endpoints will be assessed at the time of the surrogate endpoint analysis (at least the 
first 1023 randomized patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening 
of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 


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o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 


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o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main analysis 
of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all F2 and F3 patients who receive at least 1 dose of study drug. This set will be 
used to summarize safety. 
• 
Efficacy evaluable set (EES): All F2 and F3 patients in the ITT population who have taken at least 
one dose of study treatment and have a reliable liver biopsy at both baseline and at the end of the 
72 week treatment period. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all r patients who receive at least 1 dose of study drug. 
Patients in the ITT, FITT, EES, PPS, and exploratory F1 cohorts (study population and efficacy data) will be 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 


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difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. According to the method described in Ge et al. (2011)36, 
the statistical model will be used to estimate the difference (elafibranor/placebo) in rate of resolution of 
NASH without worsening of fibrosis and its 99% CI. The main confirmatory analysis will be performed when 
at least the first 1023 randomized F2/F3 patients have completed the 72 week treatment period or 
discontinued early from the study treatment. The main analysis will be based on the ITT. Supportive analysis 
will be based on the EES and PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Supplementary analyses using multiple imputations and a pattern 
mixture model will be performed, as well as sensitivity analysis using a Cochran-Mantel-Haenszel test. Further 
details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death will also be analyzed 
using an unadjusted Cox-proportional hazard’s model, log rank test and a nonparametric randomization 
based analysis of covariance method proposed by Saville and Koch.37  
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the ITT. Supportive analysis will be based on the EES and PPS. 


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9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at the 
end of the 72 week treatment period will be summarized separately by treatment group. The data will be 
analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, fibrosis 
stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the surrogate 
endpoint analysis when at least the first 1023 randomized patients with fibrosis stage F2 and F3 have 
completed the 72 week treatment period or discontinued early from the study treatment. The null hypothesis 
will be tested at the two-sided 0.01 alpha level. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant. A gatekeeping procedure will be constructed to control the overall Type I error rate for testing 
the key secondary efficacy endpoints at an overall two-sided alpha level of 0.01.  
The main analysis will be based on the IIT. Supportive analyses will be based on the EES and PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution of 
NASH without worsening of fibrosis. 
Time to event endpoints such as time to first cardiovascular event/death will be analyzed using the Cox 
proportional hazard’s model in the same manner as time to clinical event/death. 
Continuous endpoints will be analyzed using a repeated measures Analysis of Covariance (ANCOVA) model 
with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage, baseline NAS, and time-point and 
treatment by time-point interaction. A compound symmetry covariance matrix will be used for this analysis. 
The statistical model will be used to calculate the mean treatment difference and 95% confidence interval. 
If the data does not meet the required assumptions for parametric tests, the data will be analyzed using a 
nonparametric analysis of covariance method of Zink and Koch.41  
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 


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• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
• 
PNPLA3 (absence or presence of risk allele G [i.e. CC vs GG/CG], and within the at risk group, 
homozygous vs. heterozygous for the risk allel G [i.e. CG vs GG]) 
• 
Patients under statins (yes/no), defined as patients who have duration of IP exposure greater or 
equal to 60 days, with extent of exposure to statin greater than or equal to 30 days before the visit 
7 biopsy date.  
Forest plots will be generated for each of these endpoints for patients in the ITT population.  
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort and the 
FITT. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the primary 
endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided α=0.04 for 
time to clinical event/death. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant at a two-sided 1% significance level. A gatekeeping procedure will be constructed to control the 
overall Type I error rate for testing the key secondary efficacy endpoints at an overall two-sided alpha level 
of 0.01. 
The gatekeeping procedure will be detailed in the SAP and set up using the general method for building 
multi-stage parallel gatekeeping procedures in multiplicity problems with several families of null hypotheses 
(Dmitrienko and Tamhane, 2011, 2013).38,39 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected subgroups. 
In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate based 
on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for patients 
with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of at least 1023 patients provides 90% power to show that 
elafibranor is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was estimated 
to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a conservative approach, 


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no additional event rate was added for other events than histological cirrhosis or cirrhosis decompensation 
events. An annual clinical event/death rate of 7% was thus defined for the composite of both these 
endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver fibrosis. 
In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an approximate 
annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 80% power to 
show that elafibranor is superior to placebo with respect to time to clinical event/death. In order to obtain 
456 events, at least 2022 patients will be required in the IIT. 
The number of patients to be enrolled may be adjusted during the course of the study in a blinded manner 
to achieve the desired number of primary events.  This will be accomplished using standard event forecasting 
methods (Anisimov, 2011).40 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be summarized 
by worst severity and relationship to study drug. Serious AEs, and AEs leading to discontinuation will also be 
summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change from 
baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values for 
each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics.  


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9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when at least the first 1023 
randomized F2 and F3 patients complete 72 weeks of treatment or discontinue early from the study 
treatment. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. A Data integrity 
plan will be set-up to detail the blinding/unblinding process and address how data will be published in view 
of marketing authorization and how integrity of the trial will be protected. 
The DSMB will periodically review safety data from the study to ensure the well-being of study participants. 
One dedicated meeting will also be held upon availability of the surrogate endpoint analysis results.  
DSMB will be provided with data summaries that will include selected efficacy results so that the DSMB can 
assess the likely benefit-risk profile of elafibranor. These are not considered a formal interim analysis, and 
no type I error adjustments will be done for these reviews. Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target number 
of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed specifically 
for this study. The CRF being used for this study is an electronic CRF that has been fully certified as being 
compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in the 
eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized person 
and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. However these documents should be retained for a longer period if required by 
the applicable regulatory requirements or by an agreement with the Sponsor. All hospital records will be 
archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, another 
institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for clinical 
investigators, the eCRFs and instructions for their completion and return, the procedure for obtaining 
informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In addition, the Study 
Monitor will explain the Investigator’s reporting responsibilities and all applicable regulations concerning the 
clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the Sponsor 
deems is necessary to determine that data recording and protocol adherence are satisfactory. A Study 
Monitor from 
 Late Stage Development Services will be responsible for monitoring this clinical trial. 
To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent contact through 
verbal and written communication. The eCRFs and related source documents, as well as drug accountability 
will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs and Good Clinical 
Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a requirement for 
participation in this study and any other medical records required to confirm information contained in the 
eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical data 
and source document review of critical processes, and will be supported by formal remote site monitoring 
activities. Centralized monitoring activities will review study data to assess changes in individual site risk and 
to identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer questions, 
and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and 
all 
applicable 
amendments 
laid 
down 
by 
the 
World 
Medical 
Assemblies 
(APPENDIX I: World Medical Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the Sponsor 
and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be obtained 
from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in research studies. 
Prior to the study onset, the protocol, ICF, advertisements to be used for patient recruitment, and any other 
written information regarding this study to be provided to the patient or the patient’s legally acceptable 
representative must be approved by the IRB/IEC. The Sponsor will supply relevant material for the 
Investigator to submit to the IRB/IEC for the protocol’s review and approval. Verification of the IRB’s 
unconditional approval of the protocol and the written ICF statement will be transmitted to the Investigator. 
Documentation of the relevant IRB/IEC approval and of the IRB/IEC compliance with GCP guideline will be 
maintained by the site and will be available for review by the Sponsor or its designee or by the authorized 
members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a formal 
protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent protocol 
amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to the 
Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing direct 
access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, Amendments 
will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific procedures 
are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent must be 
reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC). 
The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In accordance 
with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF approved by 
the designated IRB/IEC and will be signed and personally dated by the patient or by the patient’s legally 
acceptable representative and by the person who conducted the informed consent discussion prior to 
protocol-specific procedures being performed. A separate consent form will be obtained for optional genetic 
and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by protocol 
number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall not 
be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable and 
necessary medical treatment for the injury, to the extent the expenses are not covered by the patient’s 
medical insurance, a government program, or other responsible third party. If laws or regulations of the 
locality in which the trial is taking place require additional payment of expenses, the Sponsor shall comply 
with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or paraclinical 
examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to ICH 
E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 Guideline 
for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality Assurance audit, 
the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators (or 
any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any third 
party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation of 
confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such results, 
which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the screening 
of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their studies, 
using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the manuscript 
or abstract for review by the Sponsor, and, if necessary, delay publication or communication for a limited 
time in order to protect the confidentiality or proprietary nature of any information contained therein. The 
Sponsor may also request that the Sponsor’s name and/or names of one or several of its employees appear 
or not appear in such publication. 
 
 


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15. REFERENCES LIST 
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2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
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3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin Liver 
Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
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6. Poniachik J, Santibanez C, Haim D, et al. Enhancement in liver nuclear factor-kb (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-
acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. Epub 
2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin concentrations 
and liver histology in patients with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 
2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J Gastroenterol 
Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
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12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al. Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated receptor 
(PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, 


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and increases fatty acid oxidation in moderately obese men. Diabetes. 2008;57(2):332-339. 
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regultate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485-495. 
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by PPARδ ameliorates obesity induced insulin resistance. Cell Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  
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meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol agreement and ability to predict liver-related mortality. Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
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Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-adjusted 
difference in proportions from clinical trials using logistic regression and weighted risk 
differences. Drug Information Journal, 45(4), 481-493. 
37. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
Trials Using Cox Proportional Hazards Models and Nonparametric Randomization Based 
Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
38. Dmitrienko, A., Tamhane, A.C. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011 30: 1473-1488. 
39. Dmitrienko, A., Tamhane, A.C.  General theory of mixture procedures for gatekeeping. 
Biometrical Journal. 2013 55: 402-419. 
40. Anisimov, V. Predictive event modelling in multicentre clinical trials with waiting time to 
response. Pharmaceutical Statistics. 2011; 10, 517-522. 
41. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 


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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration instructions 
X 
X 
“For Clinical Trial Use only.” 
X 
X 
“Keep out of reach of Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product and package 
return at next visit 
X 
X 
 






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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
Protocol N°: 
GFT505-315-1 / EudraCT N° 2015-005385-38/ IND n°115028 
Version number: 
5.0 
Release date: 
20 April 2020 
TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III 
Study to Evaluate the Efficacy and Safety of Elafibranor in Patients with 
Nonalcoholic Steatohepatitis (NASH) and fibrosis. 
In signing below, I give agreement to the protocol. 
International Coordinators: 
 
Signature 
Date (dd-mmm-yyyy)




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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
Protocol N°: 
 
GFT505-315-1 / EudraCT N° 2015-005385-38/ IND n°115028 
Version number: 
5.0 
Release date: 
 
20 April 2020 
TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
In signing below, I give agreement to the protocol. 
On behalf of (the Sponsor): 
GENFIT 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS – France 
Name: 
 
___
_____ 
Signature 
Date (dd-mmm-yyyy) 


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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
 
PROTOCOL TITLE: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
 
PROTOCOL NUMBER: GFT505-315-1 
 
EudraCT Number: 
2015-005385-38 
 
IND Number: 
115028  
CLINICAL PHASE: 
III  
VERSION: 
5.0 
DATE: 
20 April 2020 
 
SPONSOR: 
GENFIT, 
Parc Eurasanté, 
885 Avenue Eugène Avinée,  
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
 
INVESTIGATOR NAME: 
  
 
 
INSTITUTION NAME: 
  
 
 
INSTITUTION ADDRESS: 
  
 
 
 
 
 
SIGNATURE: 
  
 
 
DATE: 
 
/ 
/  
 
 
Day 
Month 
Year 






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SUMMARY OF CHANGES 
AMENDMENT 4: 2020 
Amendment 4 is a substantial change to address the change in definition of the primary clinical benefit endpoint and associated adjudication process.  In addition, 
updates have been made to clarify the criteria to be used to identify patients with potential DILIs. A list of adverse events of special interest has also been added 
and clarification made on the required follow-up of the potential treatment related adverse events. 
An additional section has been added to address the optional solutions put in place in case a patient participating in the RESOLVE-IT study cannot attend a site 
visit during the COVID-19 crisis or future crisis situation. 
 
Added text is bolded; deleted text is struck through. 
 
 
Summary of major changes to the protocol: 
 
Section 
New Text 
Section 1.9.2 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal hypertension/cirrhosis related events 
(liver transplantation, model end stage liver disease (MELD) score ≥15, hepatocellular carcinoma (HCC), and hospitalization due to 
occurrence of hepatic encephalopathy, or variceal bleeding, spontaneous bacterial peritonitis, and uncontrolled ascites requiring 
treatment), hepatorenal syndrome, hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive 
gastropathy [provided that these lead to hospitalization or transfusion]). 
Section 2.1.2 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a composite endpoint composed of 
death due to any cause, histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
• 
Liver transplantation 
• 
MELD score ≥15 for patients with baseline MELD score ≤12 
• 
HCC 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring hospitalization, 
o 
spontaneous bacterial peritonitis,  
o 
ascites requiring treatment. 


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hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to hospitalization 
or transfusion). 
Section 2.6 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
 
• 
SAE, AE, AESI, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
Section 3.10 
Patients who have permanently discontinued study drug due to an event listed in the primary composite endpoint for long-term efficacy 
described in Section 1.9.2 will be discontinued from the study following the EOT Visit and have no further follow-up, unless the 
patient experiences at the time of EOT visit, an ongoing adverse event possibly related to study treatment for which 
the follow-up should last until resolution of this adverse event. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, in the study and will be 
followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following the EOT Visit to report safety, diagnosis of cirrhosis 
and occurrence of clinical outcomes (as listed below) including liver and cardiovascular events until EOS or the occurrence of an event 
listed in the primary composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
 
The following procedures will be performed during the follow-up phone visit for patients who have permanently discontinued study 
drug: 
 
• 
IXRS registration. 


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• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 for patients with baseline MELD score ≤12 
o 
HCC 
o 
the onset of: 
 
variceal bleed requiring hospitalization 
 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring hospitalization 
 
spontaneous bacterial peritonitis 
 
ascites requiring treatment. 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to 
hospitalization or transfusion). 
o 
death due to any cause. 
Section 3.12  
(changes from 
protocol version 4.0) 
3.12 -OFF-SITE STUDY PROCEDURES IN CASE OF CRISIS SITUATION 
 
Based on assessment of risk, and to ensure patient safety and minimize risks to trial integrity, the sponsor determined 
that the following optional off-site study procedures can be performed in case a study participant cannot attend an on-


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site visit during the COVID-19 crisis:  
 
Safety assessment via phone call  
Local lab assessment 
Delivery of the study treatment to patient 
Visit to patient’s home  
 
These options apply to all on-site study visits except for the randomization visit (Visit 1).  Visit 1 must occur on-site as 
per section 3.7.1.   
 
These solutions can be applied depending on the investigator’s judgment of each case and the patient’s agreement. 
The alternative solutions can be implemented in response to the COVID-19 crisis prior to the notification or 
submission to and approval of regulatory agencies and ethics committees. 
 
Before implementing any of these options for a patient, the site will contact the patient to check whether he/she 
agrees with the off-site procedures. 
 
The patient will be invited to attend an on-site visit to complete the study procedures as per protocol, as soon as the 
situation allows it. 
 
In cases of any future emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure patient 
safety and minimize risks to trial integrity, after completion of a risk assessment similar measures could be taken. 
 
3.12.1 Safety and drug compliance procedures 
 
The following procedures will be performed via either a phone contact, or, if safe and possible, a direct visit to the 
patient:  
• 
Check for AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Report any change in diet and life style factors  
• 
Check concomitant/prior medication (described in Section 7.12 and 
APPENDIX III: Permitted/non-permitted medication) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous visit 
(for WOCBP only, every visit from V1) 
• 
Drug accountability  
o 
dates of any study drug interruption since the last dispensation and reason* 
o 
end of treatment (if applicable): date of last dose of study drug and reason* 
o 
end of study (if applicable) : date of end of study and reason* 
*if the reason is related to an AE, collect all required details 
• 
Physical examination if possible with a direct visit to the patient (described in Section 6.2.1)  


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• 
Record vital signs and weight if possible with a direct visit to the patient (described in Section 6.2.1 and  Section 
6.2.3) 
• 
Based on the study visit period for the patient, excluding the quality of life assessment, additional protocol related 
procedures of Section 3.7.2 or Section 3.8.1 may be performed if possible and if necessary conditions are met 
 
3.12.2 Local lab assessment  
 
The patient will be asked if he/she can access a local lab in the few days after the phone contact to obtain 
hematology, biochemistry and urinalysis testing.  
 
If a direct visit to the patient is safe and possible, the appropriate lab parameters corresponding to the on-site study 
visit as described in Table 2 will be collected. 
 
3.12.3 Delivery of study treatment to the patient 
 
The IXRS registration will be completed to trigger study drug kit assignments, and the assigned drug kits can be 
shipped to the patient, or delivered directly to the patient by the site study staff if safe and possible. 
 
As per the usual study visit, the patient will be instructed to continue taking the available tablets from the existing 
kit until he/she receives the new kit. 
 
The study drug compliance and study drug accountability will be performed as described in Section 7.10 and 
Section 7.11 once brought to the study site/study pharmacy. 
 
3.12.4 Completion of Missed Study Procedures  
 
As soon as the situation allows it, the site will schedule the patient’s on-site visit to complete the missed study 
procedures (those that could not be performed during the phone calls/visit to patient) as per protocol (see 
Section 3.7.2 or Section 3.8.1).   
 
Section 3.12  
(changes from 
Protocol version 4.2 
–US specific) 
These solutions can be applied depending on the investigator’s judgment of each case and the patient’s agreement. The alternative 
solutions can be implemented in response to the COVID-19 crisis prior to the notification or submission to and approval 
of regulatory agencies and ethics committees. 
 
Before implementing any of these options for a patient, the site will contact the patient to check whether he/she agrees with the off-site 
procedures. 
 
The patient will be invited to attend an on-site visit to complete the study procedures as per protocol, as soon as the situation allows it. 
 


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In cases of any future emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure patient 
safety and minimize risks to trial integrity, after completion of a risk assessment similar measures could be taken. 
Section 5.2.2 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for long-term efficacy evaluation 
(see Section 1.9.2), the patient will also be discontinued from the study with no further follow-up after the EOT Visit, unless the 
patient experiences at the time of EOT visit, an ongoing adverse event possibly related to study treatment for which 
the follow-up should last until resolution of this adverse event. 
Section 5.2.3 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or possibly related AEs until the 
unresolved SAEs or possibly related AEs are judged by the Investigator to have stabilized. 
Section 6.3.2 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be adjudicated by the Clinical Events 
Committee (CEC; see Section 6.5), as well as all DILI events (see  Section 6.5). 
Criteria used for reporting a potential DILI for adjudication are given below and correspond to the criteria leading to 
permanent study drug discontinuation. 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total bilirubin, and INR results meeting 
the requirements of within 8 weeks to 6 months of planned randomization visit (V1), or, using lab results from SV1 and V1 that are at 
least 8 weeks apart. 
Section 6.5 
The CEC will conduct adjudication of all disease progression events included in the primary composite efficacy long-term endpoint 
(Section 1.9.2, except for histological cirrhosis), all DILI events, and all major cardiovascular events as defined in the CEC charter. The 
CEC assessment and adjudication will occur in a blinded, consistent, and unbiased manner throughout the course of a study to determine 
whether the endpoints meet the protocol-specified criteria. 
 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist and 3 histopathologists, all of whom will be 
independent of the participants in the study. 
Section 8.1.2 
8.1.2 Adverse events of special interest (AESIs) 
 
AESIs are treatment emergent AEs corresponding to the conceptual definition of:  
 
• 
CPK elevations of severe intensity or leading to permanent study drug discontinuation 
• 
Muscle injury symptoms of severe intensity corresponding to:  


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o
Muscle pain or Myalgia
o
Muscle spasms or Tremor
o
Muscle weakness
•
Transaminases elevations from baseline of severe intensity or leading to permanent study drug discontinuation
•
Liver injury events of severe intensity corresponding to:
o
Hepatic impairment
o
Hepatic failure
•
Gastrointestinal symptoms of severe intensity corresponding to:
o
Abdominal pain
o
Constipation
o
Diarrhea
o
Nausea
o
Vomiting
o
Acute cholecystis
o
Acute pancreatitis
•
Fatigue and Asthenia of severe intensity
•
Serum creatinine elevations of severe intensity or leading to permanent study drug discontinuation
•
Renal injury events of moderate or severe intensity corresponding to:
o
Renal failure
o
Renal impairment
o
Renal colic
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are described in 
the section 8.6.1. 
Section 8.3.2 
8.3.2 Reporting a serious adverse event or an adverse event of special interest 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
AESI reporting starts from first study drug intake and ends at study end for each patient. 
Any SAE or AESI that is brought to the attention of the Investigator at any time after the reporting period and which is considered by 
him/her to be caused by the study drug within a reasonable possibility, should be reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.2 that are identified as potential primary efficacy 
endpoints for long-term evaluation will NOT be reported as SAEs unless it is determined by the adjudication committee that the event 


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does not meet the predefined criteria for an endpoint. Events that are identified as potential primary efficacy endpoints for long-term 
evaluation that are not confirmed by adjudication will be reported as described with the start of the reporting time window being the time 
of negative adjudication decision. 
 
Investigators must notify, by fax or e-mail or fax, the Sponsor designated representative 
 
of all SAEs or AESIs  IMMEDIATELY (within 24 hours of the Investigator becoming aware of the event). 
 
All SAEs or AESIs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE Form. The SAE/AESI 
Form should include a clearly written narrative describing signs, symptoms, intensity and treatment of the event, diagnostic 
procedures, as well as any relevant laboratory data and any sequelae, in order to allow a complete medical assessment of the case 
and independent determination of the possible causality. 
 
The Investigator is also required to submit follow-up SAE/AESI reports to 
 within 24 hours of becoming aware 
of additional information such as diagnosis, outcome, causality assessment, results of specific investigations, and any new significant 
information that has not been previously reported. 
 
It is critical that the information provided on the initial or follow-up SAE/AESI Form matches the information recorded in the source 
documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, autopsy reports, and other 
ANY SERIOUS ADVERSE EVENTS, OR ADVERSE EVENTS OF SPECIAL INTEREST, WHETHER OR NOT 
RELATED TO THE STUDY DRUG, MUST BE REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 
 AT THE FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
  
Email: 
 


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documents should be sent when requested and applicable. All provided reports must be anonymized. 
 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 until the event has 
subsided or, in case of permanent impairment, until the condition stabilizes. 
 
The Sponsor or its designated representative will report all the relevant safety information to the concerned Competent Authorities 
and to the Independent Ethics Committee(s) (IRB/IEC) concerned according to the country-specific requirements. 
 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics Committee in accordance 
with local regulations. 
 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical research organization (CRO) may 
be required to expedite report to the Regulatory Authorities for: 
 
• 
SAEs (including events related to study procedures) 
• 
SADRs (a serious ADR) 
• 
SUSARs (Suspected unexpected serious adverse reactions) (SUSARs) 
Section 8.3.3 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to normal, or until progression 
has been stabilized. This may imply that follow-up will continue after the patient has left the study (i.e. after EoT visit), notably for 
the potential related adverse events, and that additional investigations may be requested by the Sponsor. This information should 
be documented in the patient’s medical records. 
Section 8.5 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities that are considered clinically 
relevant by the Investigator must be recorded as an AE, AESI or SAE as applicable. 
Section 8.6.1 
The pregnancy itself is not considered an AE. 
Section 9.2.2 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, histological liver cirrhosis, 
and the full list of portal hypertension/cirrhosis related events: 
 


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• 
Liver transplantation 
• 
MELD score ≥15 for patients with baseline MELD score ≤12 
• 
HCC 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring hospitalization, 
o 
spontaneous bacterial peritonitis,  
o 
ascites requiring treatment. 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to hospitalization 
or transfusion). 
Section 9.4.2 
The main analysis will be based on the ITT. Supportive analysis will be based on the EES and PPS. 
Section 9.8 
Safety data (exposure, AEs, AESIs, clinical laboratory tests, vital signs, and ECGs) will be summarized by treatment group using 
descriptive statistics. The main summaries of safety will be based on the SS. Additional safety analysis will be based on the FSS and 
the exploratory F1 cohort. 
 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). An overall summary 
of AEs will be provided. The number and percentage of patients reporting AEs will also be presented by MedDRA System Organ Class 
and preferred term. The AEs will be summarized by worst severity and relationship to study drug. AESIs, serious AEs, and AEs leading 
to discontinuation will also be summarized. Narratives will be added for all SAEs and AESIs. 
Section 10.1 
All study required patient data generated during the study will be recorded in the eCRF, with the exception of SAE/AESI forms 
and SF-36 which will be collected via ePRO (which is then transferred to the electronic data capture). 
Section 11.1 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for clinical investigators, the 
eCRFs and instructions for their completion and return, the procedure for obtaining informed consent, and the procedure for 
reporting AEs and SAEs/AESIs with the Investigator. 


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Section 12.5 
End of the research corresponds to the end of participation (end of study EOT Visit) of last observation for the last patient 
participating in the research. 
 
 
Summary of minor changes to the protocol: 
 
The following minor changes were made to the protocol. The changes do not impact the reliability of the data generated in the clinical trial or the safety or rights of 
the subjects: 
- 
AESI has been added to the List of Abbreviations. 
- 
The version number and date were updated throughout the protocol. 
- 
Relevant sections of the synopsis were updated to keep consistency with the protocol. 
- 
Study contact details for central laboratory have been updated. 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: GENFIT 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2- [2,6-
dimethyl-4-[3-[4-(methylthio)phenyl]- 3-oxo-1(E)-
propenyl] phenoxy]-2- methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy 
and Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase:  
Phase III  
Indication:  
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
Dose level 
120 mg 
Route of administration: 
  Oral (1 tablet once daily [QD]) 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with 
fibrosis stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
Primary objective – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis 
staging system and defined as progression of at least 1 stage. 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of 
portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 for patients with a baseline MELD score ≤12 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization, 
o 
spontaneous bacterial peritonitis,  
o 
ascites requiring treatment. 
Key secondary objectives (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring. 
 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
 


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Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the 
end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according 
to NASH CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according 
to NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores 
(NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular 
inflammation], steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at 
least 1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score 
(sum of ballooning and lobular inflammation scores) according to NAS scoring and 
steatosis-activity- fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score 
(sum of ballooning and lobular inflammation scores) according to NAS scoring and 
with at least 1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score 
(sum of ballooning and lobular inflammation scores) according to steatosis-activity-
fibrosis (SAF) scoring and with at least 1 point improvement in hepatic ballooning 
o 
percentage of patients with at least 2 points improvement in disease 
activity score according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation and SAF 
activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by 
morphometry 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire) 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
Exploratory objectives 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Exploratory objectives for F1 group and the overall population (whatever the fibrosis stage – F1, F2 or 
F3) 
• 
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or 
F3), the same endpoints as for the primary and secondary objectives 


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Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 
mg: 
o 
serious adverse events, adverse events, adverse events of special interest, physical 
examination, vital signs, medical history, electrocardiogram 
o 
hematological parameters 
o 
liver markers 
o 
renal biomarkers (including urinalysis) 
o 
cardiac biomarkers 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population:  
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, 
meaning with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by 
a body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, 
or homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will 
be monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan 
measurement for presence of cirrhosis associated with biological and clinical assessments). If histological 
cirrhosis is confirmed as well as any other event listed in the long-term composite endpoint, patients will 
be discontinued from study. 
Number of estimated randomized F2-F3 Patients: at least 2022 patients (ratio 2:1) 
• 
674 patients in placebo group 
• 
1348 patients in elafibranor (GFT505) group 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as 
an exploratory arm. 
Number of participating centers (planned): ~270 centers 
Number of participating countries: 24 (Belgium, France, Germany, Italy, the Netherlands, Romania, 
Spain, UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, 
Canada, Mexico, Colombia, Argentina, Chile, Australia, South Africa) 
 
Study duration per patient: 
Estimated duration approximately 96 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week -12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of 
treatment, as described below: 
o 
Cessation of menses for at least 12 months due to ovarian failure, 


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o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure 
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of 
contraception (oral, intravaginal, or transdermal combined estrogen and progestogen 
hormonal contraception associated with inhibition of ovulation; oral, injectable, or 
implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation; or intrauterine hormone-releasing system). The hormonal contraception must 
be started at least 1 month prior to Randomization. 
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with 
at least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 
0-2, and lobular inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included 
meaning with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT 
(absence of normal value of ALT within the past year), obesity defined by a BMI ≥30, metabolic 
syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have: 
o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before Screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation). 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated 
fatty acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to 
diagnostic liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization 
(i.e., implementation of a new anti-diabetic therapy) for patients treated with 
metformin, gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, 
glucagon-like peptide (GLP)- 1 agonists, or insulin. Dose changes of these medications 
are allowed in the 6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, 
which must remain on stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment, except for glitazones which are prohibited 6 months prior to 
diagnostic liver biopsy until the end of treatment. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric 
surgery in the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive 
therapy. 
4. Type 1 diabetes patients. 
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 


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abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug   
was discontinued at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to 
Screening such as: stroke, transient ischemic attack, or coronary heart disease (angina 
pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging 
system are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is 
typically defined as higher than 20 g pure alcohol per day. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic 
procedures including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection 
or positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance 
with the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or 
five half-lives, whichever is longer, prior to Screening. 
Concomitant medications: 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, 
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the 
dosage has been kept constant for at least 2 months prior to Screening. 
19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted 
to: corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), 
tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 
days prior to Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, 
distribution, metabolism, or excretion or could lead to induction or inhibition of microsomal 
enzymes, e.g., indomethacin, which are not permitted from Randomization until end of 
treatment. 
Associated illnesses or conditions: 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
24. Positive anti-human immunodeficiency virus antibody. 


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25. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease 
patients are allowed into the study. 
27. International normalized ratio >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 
29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as 
patients with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less 
than 60 ml/min/1.73 m2). 
31. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated 
CPK >3 x the ULN, the measurement can be repeated prior to Randomization. In this case, 
retest should be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads 
to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without 
worsening of fibrosis after 72 weeks of treatment. 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of 
portal hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 for patients with a baseline MELD score ≤12 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization, 
o 
spontaneous bacterial peritonitis, 
o 
ascites requiring treatment. 
 
The final analysis will be performed when 456 patients experience an event listed above. This is 
expected to occur approximately 96 months after the first patient is randomized. 
Key secondary endpoints (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring 
at 72 weeks. 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL 
cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
Other secondary endpoints 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the 
end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH 
CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring 
system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 
point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score 


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(sum of ballooning and lobular inflammation scores) according to NAS scoring and 
steatosis-activity-fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis 
(SAF) scoring and with at least 1 point improvement in hepatic ballooning 
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by 
morphometry. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Study Duration (planned): estimated 96 months (First Patient First Visit [FPFV]-Last patient last visit 
[LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – Sep 2018 
• 
Recruitment period: March 2016 – May 2020 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q1 2020 – Q2 2020 
• 
LPLV (LTTP): estimated within Q1 2024 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in 
the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint, all drug-induced liver injury events, and all major cardiovascular events as 
defined in the CEC charter. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, 1 endocrinologist, and 3 histopathologists
all of whom will be independent of the participants in the study. 
 
 








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central pathologist must be performed at least 4 weeks before Randomization, in order to obtain the results in time. However, in some exceptional cases, the 
central reading process can be expedited allowing a shorter time between SV1 or SV2 and V1. Coagulation (platelet count and PT [INR]) should be checked 
locally prior to this liver biopsy (according to local medical standards in each hospital). 
 
- 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the patients 
5. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to 
Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control). 
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. 
In the LTTP the first ECG will be performed at V9 and then every 48. 
11. 
Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological 
assessment).  In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed 
locally before the biopsy. 
12. 
QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, 
respectively), and every 48 weeks thereafter. 
13. 
EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or 
trial discontinuation). 








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5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the 
pharmacogenomic and biomarker ICF. 
6. 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1) are 
available, then SV1 and V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits should be 
scheduled in order to obtain the needed results prior to the randomization. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy 


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Figure 1: STUDY DURATION AND VISIT SCHEDULE 


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Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
  


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 5. 0 2 0 A pril 2 0 2 0  
G E N F I T  
C O N FI D E N TI A L  
P a g e 3 7  of 1 44 
T A B L E O F C O N T E N T S  
 
C LI NI C A L P R O T O C O L – P H A S E 3  ....................................................................................................... 1 
C LI NI C A L S T U D Y P R O T O C O L SI G N A T U R E P A G E  .................................................................................. 2 
C LI NI C A L S T U D Y P R O T O C O L SI G N A T U R E P A G E  .................................................................................. 3 
C LI NI C A L S T U D Y P R O T O C O L SI G N A T U R E P A G E  .................................................................................. 4 
C L I N I C A L S T U D Y P R O T O C O L S I G N A T U R E P A G E  ......................................................................... 5 
C LI NI C A L S T U D Y P R O T O C O L I N V E S TI G A T O R SI G N A T U R E P A G E  .......................................................... 6 
S T U D Y C O N T A C T S  ............................................................................................................................ 7 
S U M M A R Y O F C H A N G E S  .................................................................................................................... 9 
C LI NI C A L T RI A L S Y N O P SI S  .............................................................................................................  2 0  
T a bl e  1:  
S T U D Y G E N E R A L A S S E S S M E N T  S C H E D U L E  .............................................................. 2 7  
T a bl e  2:  
S T U D Y BI O L O GI C A L A S S E S S M E N T  S C H E D U L E  .......................................................... 3 1  
Fi g ur e  1:  
S T U D Y D U R A TI O N A N D VI SI T  S C H E D U L E  ................................................................ 3 5  
Fi g ur e 2:  
P R E G N A N C Y T E S TI N G S C H E D U L E F O R W O M E N O F C HI L D B E A RI N G P O T E N TI A L  ......... 3 6  
T A B L E O F C O N T E N T S  .....................................................................................................................  3 7  
T A B L E O F T A B L E S  ..........................................................................................................................  4 3  
T A B L E O F FI G U R E S  ........................................................................................................................  4 4  
LI S T O F A B B R E VI A TI O N S  ................................................................................................................  4 5  
1.  
I N T R O D U C TI O N ...............................................................................................................  4 8  
1. 1.  N O N A L C O H O L I C  S T E A T O H E P A T I T I S  ............................................................................ 4 8  
1. 2.  P A T H O P H Y S I O L O G I C A L P R O C E S S O F N O N A L C O H O L I C  S T E A T O H E P A T I T I S  .............. 4 8  
1. 3.  E L A F I B R A N O R: R A T I O N A L E F O R A M I X E D P P A R A L P H A / D E L T A A G O N I S T I N  N A S H  . 5 0  
1. 4.  S U M M A R Y O F N O N C L I N I C A L  S T U D I E S  ........................................................................ 5 1  
1. 4. 1.  
P h ar m a c ol o g y  ........................................................................................................ 5 1  
1. 4. 2.  
S af et y  p h ar m a c ol o g y  .............................................................................................. 5 1  
1. 4. 3.  
A bs or pti o n/ distri b uti o n/ m et a b olis m/ e x cr eti o n st u di es  ( A D M E) .................................... 5 1  
1. 4. 4.  
T o xi c ol o g y  .............................................................................................................  5 2  
1. 4. 4. 1  M ut a g e ni cit y a n d  g e n ot o xi cit y  ................................................................................. 5 2  
1. 4. 4. 2  Ac ut e t o xi cit y  ....................................................................................................... 5 2  
1. 4. 4. 3  R e p e at e d d os e t o xi cit y st u di es  ................................................................................ 5 3  
1. 4. 4. 4  P h ot ot o xi cit y st u di es  ............................................................................................. 5 3  
1. 5.  C L I N I C A L  S T U D I E S  ....................................................................................................... 5 3  
1. 5. 1.  
N A S H  ....................................................................................................................  5 3  
1. 5. 2.  
P B C  ......................................................................................................................  5 4  
1. 6.  C O N C L U S I O N  ................................................................................................................  5 4  
1. 7.  R A T I O N A L E F O R S T U D Y  P O P U L A T I O N  ......................................................................... 5 5  
1. 8.  J U S T I F I C A T I O N O F T H E S E L E C T E D  D O S E  .................................................................... 5 6  


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 5. 0 2 0 A pril 2 0 2 0  
G E N F I T  
C O N FI D E N TI A L  
P a g e 3 8  of 1 44 
1. 9.  R A T I O N A L E F O R E F F I C A C Y  E N D P O I N T  ........................................................................ 5 6  
1. 9. 1.  
Pri m ar y e n d p oi nt f or a p pli c ati o n u n d er c o n diti o n al  a p pr o v al  ....................................... 5 6  
1. 9. 2.  
Pri m ar y e n d p oi nt f or cli ni c al o ut c o m e ( p ost a p pr o v al  c o nfir m ati o n)  .............................. 5 6  
1. 1 0.  R A T I O N A L E F O R S T U D Y  D U R A T I O N  ............................................................................. 5 7  
1. 1 1.  R A T I O N A L E F O R S A F E T Y  M O N I T O R I N G  ....................................................................... 5 7  
2.  
T RI A L  O BJ E C TI V E S  ...........................................................................................................  5 9  
2. 1.  P R I M A R Y  O B J E C T I V E S  .................................................................................................. 5 9  
2. 1. 1.  
S urr o g at e e n d p oi nt  a n al ysis  .................................................................................... 5 9  
2. 1. 2.  
L o n g -t er m e n d p oi nt  ................................................................................................ 5 9  
2. 2.  K E Y S E C O N D A R Y O B J E C T I V E S – A T S U R R O G A T E E N D P O I N T  A N A L Y S I S  .................... 5 9  
2. 3.  O T H E R S E C O N D A R Y  O B J E C T I V E S  ................................................................................. 6 0  
2. 4.  E X P L O R A T O R Y  O B J E C T I V E S  ......................................................................................... 6 1  
2. 5.  E X P L O R A T O R Y   O B J E C T I V E S   F O R   F 1   G R O U P   A N D   T H E   O V E R A L L     
P O P U L A T I O N  .................................................................................................................  6 1  
2. 6.  S A F E T Y S E C O N D A R Y  O B J E C T I V E S  ................................................................................ 6 1  
3.  
T RI A L  D E SI G N  ..................................................................................................................  6 2  
3. 1.  N U M B E R O F  P A T I E N T S .................................................................................................. 6 2  
3. 2.  M E T H O D O F A S S I G N I N G P A T I E N T T O T R E A T M E N T  G R O U P  ........................................ 6 2  
3. 3.  D O S E A D J U S T M E N T  C R I T E R I A  ..................................................................................... 6 3  
3. 4.  D U R A T I O N O F S T U D Y  P A R T I C I P A T I O N  ....................................................................... 6 3  
3. 5.  S T U D Y  P E R I O D S  ............................................................................................................  6 3  
3. 6.  S C R E E N I N G P E R I O D ( W E E K -1 2 T O W E E K  -1 )  ............................................................. 6 3  
3. 6. 1.  
S cr e e ni n g visits S V 1 a n d  S V 2 .................................................................................. 6 3  
3. 6. 2.  
S cr e e ni n g Visit S V 2 (li v er bi o ps y if r e q uir e d, W e e k -1 2 t o r e c o m m e n d e d W e e k  -4):  ..... 6 5  
3. 6. 3.  
S cr e e ni n g P h o n e Visit S P V ( W e e k  -1):  ...................................................................... 6 5  
3. 7.  F I R S T T R E A T M E N T P E R I O D ( W E E K 0 T O W E E K  7 2 )  .................................................... 6 5  
3. 7. 1.  
R a n d o miz ati o n Visit V 1 ( W e e k  0):  ............................................................................ 6 6  
3. 7. 2.  
First Tr e at m e nt P eri o d visits V 1 t o V 7 ( W e e k 0 t o W e e k  7 2):  ...................................... 6 6  
3. 8.  L O N G -T E R M T R E A T M E N T  P E R I O D  ................................................................................ 6 7  
3. 8. 1.  
L o n g -t er m Tr e at m e nt P eri o d visits ( V 8 t o V n)  ........................................................... 6 7  
3. 8. 2.  
L o n g -t er m Tr e at m e nt P eri o d p h o n e visits ( P V 1 t o P V n)  .............................................. 6 8  
3. 9.  E N D O F S T U D Y T R E A T M E N T  V I S I T  ............................................................................... 6 8  
3. 1 0.  F O L L O W -U P F O R P A T I E N T S W H O H A V E P E R M A N E N T L Y D I S C O N T I N U E D S T U D Y  
D R U G  6 9  
3. 1 1.  O P T I O N A L  V I S I T S  ......................................................................................................... 7 0  
3. 1 1. 1.  
R et e sti n g s cr e e ni n g  visits  ........................................................................................ 7 0  
3. 1 1. 2.  
U ns c h e d ul e d  visits  .................................................................................................. 7 1  
3. 1 2.  O F F- S I T E S T U D Y P R O C E D U R E S I N C A S E O F C R I S I S S I T U A T I O N  ............................... 7 1  
3. 1 2. 1.  
S af et y a n d dr u g c o m pli a n c e pr o c e d ur es  ................................................................... 7 2  
3. 1 2. 2.  
L o c al l a b ass ess m e nt  .............................................................................................. 7 2  
3. 1 2. 3.  
D eli v er y of st u d y tr e at m e nt t o t h e p ati e nt  ................................................................ 7 2  


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 5. 0 2 0 A pril 2 0 2 0  
G E N F I T  
C O N FI D E N TI A L  
P a g e 3 9  of 1 44 
3. 1 2. 4.  
C o m pl eti o n of Miss e d St u d y Pr o c e d ur es  ................................................................... 7 3  
3. 1 3.  E X P L O R A T O R Y / A N C I L L A R Y  S U B S T U D Y  ....................................................................... 7 3  
4.  
P A TI E N T  S E L E C TI O N  ........................................................................................................ 7 4  
4. 1.  I N C L U S I O N  C R I T E R I A  .................................................................................................. 7 4 
4. 2.  E X C L U S I O N  C R I T E R I A  .................................................................................................. 7 5  
5.  
T RI A L  P R O C E D U R E S  ......................................................................................................... 7 8  
5. 1.  L I F E S T Y L E R E C O M M E N D A T I O N S A N D S T U D Y  R E C O M M E N D A T I O N S  .......................... 7 8  
5. 1. 1.  
St a n d ar d di et a n d e x er cis e  r e c o m m e n d ati o ns ........................................................... 7 8  
5. 1. 2.  
Di et ar y, fl ui d, a n d lif est yl e  r estri cti o ns ...................................................................... 7 8  
5. 1. 3.  
H o m e pr e g n a n c y t est f or w o m e n of c hil d b e ari n g  p ot e nti al  ......................................... 7 9  
5. 1. 4.  
S u n  e x p os ur e  ......................................................................................................... 7 9  
5. 2.  P A T I E N T W I T H D R A W A L A N D P A T I E N T T R E A T M E N T D I S C O N T I N U A T I O N  R U L E S  ...... 7 9  
5. 2. 1.  
H a n dli n g of p ati e nt  wit h dr a w al  ................................................................................ 7 9  
5. 2. 2.  
P er m a n e nt dis c o nti n u ati o ns of st u d y  dr u g  ................................................................ 7 9  
5. 2. 3.  
P ati e nt dis c o nti n u ati o n fr o m t h e  St u d y  ..................................................................... 8 0  
5. 2. 4.  
P ati e nts l ost t o  f oll o w-U p  ........................................................................................ 8 1  
5. 2. 5.  
R e pl a c e m e nt  ......................................................................................................... 8 1  
5. 2. 6.  
Pr e m at ur e dis c o nti n u ati o n of t h e  st u d y .................................................................... 8 1  
5. 3.  P A T I E N T  R E S C R E E N I N G  ............................................................................................... 8 1  
6.  
A S S E S S M E N T S .................................................................................................................  8 3  
6. 1.  E F F I C A C Y A N D S A F E T Y  A S S E S S M E N T S  ........................................................................ 8 3  
6. 1. 1.  
Hist ol o gi c al  ass ess m e nts  ......................................................................................... 8 3  
6. 1. 1. 1  R e c o m m e n d ati o ns  r el at e d t o li v er bi o ps y  ................................................................ 8 3  
6. 1. 1. 2  Li v er bi o ps y r e a di n g f or N A S a n d N A S H C R N fi br osis s c or e  ..................................... 8 4  
6. 1. 2.  
Bi ol o gi c al  ass ess m e nts  ............................................................................................ 8 4  
6. 1. 2. 1  L a b or at or y ass ess m e nts  ...................................................................................... 8 5  
6. 1. 2. 2  Uri n ar y pr e g n a n c y t ests  ....................................................................................... 8 5  
6. 1. 2. 3  S er ol o g y ( S B 1)  ................................................................................................... 8 5  
6. 1. 2. 4  Ot h er p ar a m et ers  ............................................................................................... 8 5  
6. 1. 3.  
C o nstit uti o n of  bi o b a n k  ........................................................................................... 8 5  
6. 2.  O T H E R S A F E T Y A S S E S S M E N T S A N D O N G O I N G S A F E T Y  M O N I T O R I N G  ...................... 8 6  
6. 2. 1.  
P h ysi c al  e x a mi n ati o n  .............................................................................................. 8 6  
6. 2. 2.  
W aist  cir c u mf er e n c e  ............................................................................................... 8 6  
6. 2. 3.  
Vit al  si g ns ..............................................................................................................  8 6  
6. 2. 3. 1  I m p ort a nt p oi nts f or cli ni c al bl o o d pr ess ur e m e as ur e m e nt  ........................................... 8 6  
6. 2. 4.  
El e ctr o c ar di o gr a m  .................................................................................................. 8 7  
6. 2. 5.  
Fi br o S c a n ..............................................................................................................  8 7  
6. 2. 6.  
Q u alit y of lif e  q u esti o n n air e  ..................................................................................... 8 7  
6. 3.  I M P O R T A N T S P E C I F I C B I O L O G I C A L C O N S I D E R A T I O N S A N D P A T I E N T 
D I S C O N T I N U A T I O N  R U L E S   .......................................................................................... 8 7  


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6.3.1. 
Creatine phosphokinase .......................................................................................... 87 
6.3.2. 
Liver function monitoring ........................................................................................ 88 
6.3.2.1 
Monitoring of patients with normal baseline aminotransferase values ............................ 88 
6.3.2.2 
Monitoring of patients with increased baseline aminotransferase values ........................ 89 
6.3.3. 
Threshold for diagnosis of cirrhosis .......................................................................... 89 
6.4. SAFETY & EFFICACY DATA REVIEW .............................................................................. 90 
6.5. CLINICAL EVENT COMMITTEE ...................................................................................... 90 
6.6. GUIDANCE FOR INVESTIGATORS ................................................................................. 90 
6.6.1. 
Summary of safety data .......................................................................................... 90 
6.6.2. 
Safety data conclusion ............................................................................................ 93 
6.6.3. 
Benefit/risk assessment .......................................................................................... 93 
7. 
TREATMENTS ................................................................................................................... 95 
7.1. DESCRIPTION OF STUDY MEDICATIONS ..................................................................... 95 
7.2. PACKAGING AND LABELING ......................................................................................... 95 
7.2.1. 
Packaging ............................................................................................................. 95 
7.2.2. 
Labeling ................................................................................................................ 95 
7.3. DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ........................... 96 
7.4. METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ........................................ 96 
7.5. STORAGE CONDITIONS ................................................................................................ 96 
7.6. DISPENSING OF TREATMENT ....................................................................................... 96 
7.7. TREATMENT REPLACEMENT .......................................................................................... 97 
7.8. PROCEDURE FOR BLINDING......................................................................................... 97 
7.9. PROCEDURE FOR UNBLINDING .................................................................................... 97 
7.10. STUDY DRUG COMPLIANCE .......................................................................................... 97 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION ............................... 98 
7.12. OTHER MEDICATION..................................................................................................... 98 
7.12.1. 
Handling of concomitant medication......................................................................... 98 
7.12.2. 
Non-permitted medication ...................................................................................... 98 
7.12.3. 
Permitted medication under condition ...................................................................... 99 
7.12.4. 
Permitted medication ............................................................................................ 100 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT ................................................................ 101 
8.1. 
DEFINITIONS .............................................................................................................. 101 
8.1.1. 
Adverse events .................................................................................................... 101 
8.1.2. 
Adverse events of special interest (AESIs) .............................................................. 102 
8.1.3. 
Serious adverse events ......................................................................................... 103 
8.1.3.1 
Life-threatening adverse events ......................................................................... 103 
8.1.3.2 
Inpatient or prolonged hospitalization ................................................................. 103 
8.1.3.3 
Significant or incapacitating disability .................................................................. 104 
8.1.3.4 
Medically important conditions ........................................................................... 104 
8.1.4. 
Clarification on serious adverse events: .................................................................. 104 


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 5. 0 2 0 A pril 2 0 2 0  
G E N F I T  
C O N FI D E N TI A L  
P a g e 4 1  of 1 44 
8. 1. 5.  
A d v ers e dr u g  r e a cti o n ........................................................................................... 1 0 4  
8. 1. 6.  
U n e x p e ct e d a d v ers e  e v e nt  .................................................................................... 1 0 5  
8. 2.  A S S E S S M E N T S  .............................................................................................................  1 0 5  
8. 2. 1.  
I nt e nsit y ass ess m e nt  ............................................................................................ 1 0 5  
8. 2. 2.  
R el ati o n t o t h e st u d y  tr e at m e nt ............................................................................. 1 0 5  
8. 2. 3.  
A cti o n t a k e n a n d  o ut c o m e ..................................................................................... 1 0 6  
8. 3.  R E P O R T I N G  .................................................................................................................  1 0 6  
8. 3. 1.  
R e p orti n g a n a d v ers e  e v e nt  .................................................................................. 1 0 7  
8. 3. 2.  
R e p orti n g a s eri o us a d v ers e  e v e nt or a n a d v ers e e v e nt of s p e ci al i nt er est  ................. 1 0 7  
8. 3. 3.  
F oll o w -u p  ............................................................................................................  1 0 9  
8. 4.  P O S T S T U D Y R E P O R T I N G  R E Q U I R E M E N T S  ............................................................... 1 0 9  
8. 5.  C L I N I C A L L A B O R A T O R Y A B N O R M A L I T I E S A N D O T H E R A B N O R M A L A S S E S S M E N T S 
A S A D V E R S E E V E N T S O R S E R I O U S A D V E R S E  E V E N T S  ............................................... 1 0 9  
8. 6.  S P E C I A L S I T U A T I O N  R E P O R T S ................................................................................... 1 0 9  
8. 6. 1.  
Pr e g n a n c y  ...........................................................................................................  1 0 9  
8. 6. 2.  
M e di c ati o n  err or  ................................................................................................... 1 1 0  
8. 6. 3.  
M is us e ................................................................................................................  1 1 0  
8. 6. 4.  
O v er d os e  ............................................................................................................  1 1 0  
8. 6. 5.  
A b us e  .................................................................................................................  1 1 0  
9.  
S T A TI S TI C A L M E T H O D S A N D D A T A  A N A L Y SI S  .................................................................. 1 1 1  
9. 1.  R A N D O M I Z A T I O N A N D T R E A T M E N T  A S S I G N M E N T  ................................................... 1 1 1  
9. 2.  E N D P O I N T S  .................................................................................................................  1 1 1  
9. 2. 1.  
S urr o g at e e n d p oi nt - r es ol uti o n of N A S H  ................................................................ 1 1 1  
9. 2. 2.  
L o n g -t er m e n d p oi nt – ti m e t o cli ni c al e v e nt/ d e at h  ................................................... 1 1 1  
9. 2. 3.  
K e y S e c o n d ar y  E n d p oi nts  ...................................................................................... 1 1 2  
9. 2. 4.  
Ot h er S e c o n d ar y  E n d p oi nts  ................................................................................... 1 1 2  
9. 2. 5.  
E x pl or at or y  e n d p oi nts  ........................................................................................... 1 1 3  
9. 3.  A N A L Y S I S  S E T S  ...........................................................................................................  1 1 4  
9. 4.  A N A L Y S I S O F P R I M A R Y  E N D P O I N T S  ......................................................................... 1 1 4  
9. 4. 1.  
R es ol uti o n of  N A S H  .............................................................................................. 1 1 4  
9. 4. 2.  
L o n g -t er m e n d p oi nts  ............................................................................................ 1 1 5  
9. 5.  O T H E R S T A T I S T I C A L  A N A L Y S I S  ................................................................................. 1 1 5  
9. 5. 1.  
K e y s e c o n d ar y  e n d p oi nt  ........................................................................................ 11 5  
9. 5. 2.  
Ot h er s e c o n d ar y  e n d p oi nts  ................................................................................... 1 1 6  
9. 5. 3.  
S u b gr o u p  a n al ys es  ............................................................................................... 1 1 6  
9. 5. 4.  
E x pl or at or y  a n al ys es  ............................................................................................. 1 1 6  
9. 6.  S T R A T E G I E S T O C O N T R O L T Y P E I  E R R O R  ................................................................. 1 1 7  
9. 7.  S A M P L E S I Z E  C A L C U L A T I O N  ...................................................................................... 1 1 7  
9. 7. 1.  
R es ol uti o n of  N A S H  .............................................................................................. 1 1 7  
9. 7. 2.  
Ti m e t o cli ni c al  e v e nt/ d e at h  .................................................................................. 1 1 8  




Clinical Trial GFT505-315-1 
 Protocol V5.0 20 April 2020
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TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
27 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
31 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day (MTD) 
92 


Clinical Trial GFT505-315-1 
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TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
35 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
36 


Clinical Trial GFT505-315-1  
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LIST OF ABBREVIATIONS 
 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase 
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 


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FSS 
full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IQR 
InterQuartile Range 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFL 
nonalcoholic fatty liver 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III 
PBC 
Primary Biliary Cholangitis 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis-activity- fibrosis 


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 5. 0 2 0 A pril 2 0 2 0  
G E N F I T  
C O N FI D E N TI A L  
P a g e 4 7  of 1 44 
 
 
S A P  
St atisti c al A n al ysis Pl a n  
S B x  
s cr e e ni n g bi ol o gi c al ass ess m e nt visit  
S F -3 6  
3 6 -It e m S h ort-F or m H e alt h S ur v e y  
S G L T 2  
s o di u m/ gl u c os e c otr a ns p ort er 2  
S O P  
St a n d ar d O p er ati n g Pr o c e d ur e  
S S  
s af et y s et  
S U S A R  
s us p e ct e d u n e x p e ct e d s eri o us a d v ers e r e a cti o ns  
S V x  
S cr e e ni n g Visit x  
T L C  
t h er a p e uti c lif est yl e c h a n g e 
T N F  
T u m or N e cr osis F a ct or -al p h a  
U D C A  
Urs o D e o x y C h oli c A ci d  
U L N  
u p p er li mit of n or m al  
U V -L L N A  
U V - L o c al L y m p h N o d e Ass a y  
V x  
Visit x  
W O C B P  
w o m e n of c hil d b e ari n g p ot e nti al  
 
 


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1. INTRODUCTION 
 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% 
to 16% in Europe and from 6% to 15% in the US. 
 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR 
can be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in disease 
progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing injurious 
and fibrotic mechanisms resulting in disease progression, it should not be considered a sole therapeutic 
target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the “second 
hits.” 
 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 
Lipid peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by- products of cellular apoptosis, are also increased in these groups of patients. 


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1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the fibrate 
class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis and 
upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in serum 
triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in cholesterol 
efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and C-reactive 
protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like Methionine-
Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with fibrates in human 
NASH have been unimpressive. For example in a pilot study, 12 months treatment with clofibrate in 16 
patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or triglycerides 
levels.14 
 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
 


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The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
 
1.4.1. 
Pharmacology 
 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic treatment 
of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic plaques in 
the aorta. 
 
1.4.2. 
Safety pharmacology 
 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried 
by the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted 
into the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 


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and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. Thus, 
the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug metabolism 
should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed through a clinical 
study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of elafibranor 120 
mg administered for 14 days alone or with a single administration of warfarin. This study demonstrated 
that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-warfarin). 
 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not saturable. 
 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal metabolite 
GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the potential for 
drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, elafibranor 
(GFT505) has recently been assessed in a follow-up clinical DDI study with the OATP1B3-sensitive 
substrate, atorvastatin. 
 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no evidence 
of the formation of unique human metabolites or metabolites formed at disproportionately higher levels 
in human hepatocytes than in any other species. 
 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
 
1.4.4. 
Toxicology 
 
1.4.4.1 
Mutagenicity and genotoxicity 
 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
 
1.4.4.2 
Acute toxicity 
 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 


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administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose 
of 1000 mg/kg. 
 
1.4.4.3 
Repeated dose toxicity studies 
 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year repeated-
dose carcinogenicity studies in mice and rats have been completed. 
 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). However, 
it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive to PPARα 
agonist induced peroxisome proliferation and associated liver side effects. Thus, available information on 
this class of drug which includes marketed fibrates together with the lack of any liver side effects in monkeys 
treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 Overall, these 
studies did not reveal any other safety issues up to the highest doses tested. Notably, elafibranor did not 
have any of the known PPARγ-related concerns such as excess in weight gain, hemodilution, edema, 
cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
 
1.4.4.4 
Phototoxicity studies 
 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 
 
1.5. 
CLINICAL STUDIES 
 
1.5.1. 
NASH 
 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 completed clinical trials, and 5 still ongoing. A total of 561 healthy lean subjects,    
60 overweight or obese subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease 
and 20 with hepatic impairment (Child-Pugh class A, B or C) have been randomized to date in the 
completed trials. Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up 
to 16 days. 
 
A Phase 2 program was initiated to assess the safety and efficacy profile of elafibranor in subjects with 
cardiometabolic disorders and NASH. To date, 5 Phase 2a studies have been completed, in which 297 


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subjects were randomized: 37 with mixed hyperlipidemia (type IIb Frederickson); 94 with atherogenic 
dyslipidemia and abdominal obesity; 47 with impaired glucose tolerance and abdominal obesity; 97 with 
diabetes mellitus type II; and 22 with insulin resistance and abdominal obesity. A Phase 2b study has also 
been completed, in which 274 subjects with NASH were randomized. In the Phase 2 program, the elafibranor 
daily doses ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months. 
 
A Phase 2a randomized, open-label, sequential cohort study (GFT505E-218-1) will assess the PK and 
pharmacodynamic (PD) profile and the safety and tolerability of two dose levels of GFT505 (80 mg and 
120 mg) in children and adolescents, 8 to 17 years of age, with NASH. In this study, subjects will receive 
80 or 120 mg of GFT505 once daily for 12 weeks. The study consists of two paediatric patient cohorts 
with NASH which will be dosed sequentially. Cohort 1 will consist of +/- 12 subjects who are ≥12 to ≤17 
years of age. Once 10 subjects in cohort 1 have been evaluated for PK and safety through Visit 4 (30 
days) by an independent Data Safety Monitoring Board (DSMB), enrollment will be open to subjects ≥8 
to ≤11 years of age. Cohort 2 will consist of +/- 8 subjects who are ≥8 to ≤11 years of age. 
 
At time of DSUR data lock point (31 July 2019), 1 subject (≥12 to ≤17 years of age) had been enrolled and 
exposed to at least one administration of GFT505. 
 
A Phase 2 study (GFT505-219-8) to evaluate the effect of a 6-week elafibranor (120 mg) treatment 
administered once daily on hepatic lipid composition in subjects with nonalcoholic fatty liver (NAFL) is 
currently ongoing. This study intends to achieve mechanistic information about the mode of action of 
elafibranor on the (lipid) metabolism in the human fatty liver. Subjects with NAFL will receive 120 mg of 
GFT505 or placebo once daily for 6 weeks in randomized order in a crossover design. Overall, 16 subjects 
with NAFL are intended to be included. 
 
For additional information see Investigator’s Brochure. 
 
1.5.2. 
PBC 
 
Based on the mechanism of action of elafibranor, and on the relevant efficacy and safety data collected 
to date, specifically on decrease in ALP and inflammation markers, a Phase 2a study has been launched in 
PBC has been completed, under IND 132202, filed in September 2016. The aim of this study was to 
validate the efficacy of elafibranor on ALP decrease in this patient population, and to confirm its safety in 
a population with PBC. This study was designed to compare the effect of daily oral administration for 12 
weeks of GFT505 80 mg and 120 mg on changes in serum alkaline phosphatase (ALP) to that of placebo 
in subjects with PBC and inadequate response to ursodeoxycholic acid (UDCA). 
 
For additional information see Investigator’s Brochure. 
 
 
1.6. 
CONCLUSION 
 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 


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such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. 
 
Moreover at the last DSUR cut-off date (31 July 2019), 25 clinical studies with elafibranor have been 
conducted or are ongoing (in which a total of 3245 subjects have been randomized, including an estimated 
2206 subjects exposed to elafibranor. In general, the treatment was well tolerated. No interaction, 
medication errors, or abuse/misuse cases have been reported to this date. See Section 6.6 for further 
information. 
 
For additional information see Investigator’s Brochure. 
 
1.7. 
RATIONALE FOR STUDY POPULATION 
 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can progress 
to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with mild to 
moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed cirrhosis.21 
 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) 
in the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based 
on the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the evaluation 
of long-term outcomes including progression to cirrhosis should ensure that an expected number of 
events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
 
As a conservative approach, no supplementary percentage was added to the estimated progression rate 
to histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
 


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A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
 
To support this assumption, a dose-response modeling was performed based on data obtained in the Phase 
I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In this model, 
the studied response was the change at endpoint versus baseline in biochemical parameters known to be 
associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes (ALT, GGT, 
alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based on this 
modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its good 
safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg elafibranor 
appears to be the most appropriate dose for the upcoming Phase III trial. 
 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
 
1.9.1. 
Primary endpoint for application under conditional approval 
 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, 
a slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as 
liver failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of 
steatohepatitis,28 i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not 
associated with increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. 
Natural history studies are now available showing that patients with steatohepatitis but not those with 
steatosis only (i.e., nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. 
This forms the basis for "resolution of NASH" as a desirable outcome of therapy in the short-term; a 
concept widely embraced by the academic community and expressed in several scientific society endorsed 
position papers.29,30 Based on the recently published recommendations from this workshop,30 resolution of 
NASH with no worsening of fibrosis may be an acceptable surrogate endpoint suitable for a Phase III 
enrolling patients with NASH and fibrosis.  Based on recent data that have shown that fibrosis stage of 2 
or more is related to liver-related mortality,22 the “no worsening of fibrosis” should be no progression of 
one stage in fibrosis. 
 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
 


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The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint). 
 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15,  and hospitalization due to occurrence of hepatic encephalopathy or variceal bleeding, spontaneous 
bacterial peritonitis, and uncontrolled ascites requiring treatment).  
 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most accurate 
estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 2145.5 person- 
years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had 
an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a population of patients 
with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 0.14 stage/year in a 
population of patients with NASH. In another study of 108 patients, no significant difference in the 
proportion exhibiting fibrosis progression was found between those with NAFLD or NASH.31 In the whole 
cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths between 
treatment and control groups can be considered as a potential clinically meaningful outcome measure for 
clinical trials. This long-term outcome including progression to cirrhosis is considered acceptable,30 and 
required in a postapproval study for treatments approved under conditional approval. 
 
1.10. RATIONALE FOR STUDY DURATION 
 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH without 
worsening of fibrosis. 
 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate 
and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from 
recently published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33 
1.11. RATIONALE FOR SAFETY MONITORING 
 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the chronic 
toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of elafibranor 
does not reveal any major safety concern, based on the conclusion that elafibranor-induced liver toxicity in 
rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year but 
improvement of liver function markers) and humans (consistent improvement of liver function markers in 
all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on the 


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liver effects of PPAR agonists. 
 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine ratio, 
cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, kidney 
injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 
will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the DSMB. 
In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored throughout the 
study. 
 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with 
fibrosis stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
 
2.1. 
PRIMARY OBJECTIVES 
 
2.1.1. 
Surrogate endpoint analysis 
 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis 
staging system and defined as progression of at least 1 stage. 
 
2.1.2. 
Long-term endpoint 
 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
 
• 
Liver transplantation 
• 
MELD score ≥15 for patients with baseline MELD score ≤12 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization, 
o 
spontaneous bacterial peritonitis,  
o 
ascites requiring treatment. 
 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS 
 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 


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HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
 
2.3. 
OTHER SECONDARY OBJECTIVES 
 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end 
of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH 
CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring 
system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 
point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and steatosis-
activity- fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to SAF scoring and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 


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o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events 
 
2.4. 
EXPLORATORY OBJECTIVES 
 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION 
(WHATEVER THE FIBROSIS STAGE – F1, F2 OR F3) 
 
• 
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or 
F3), the same endpoints as for the primary and secondary objectives. 
 
2.6. 
SAFETY SECONDARY OBJECTIVES 
 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
 
• 
SAE, AE, AESI, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 


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3. 
TRIAL DESIGN 
 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. 
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by 
a LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed 
in the composite endpoint for long term efficacy evaluation. 
 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 
2 diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
 
3.1. 
NUMBER OF PATIENTS 
 
It is planned to randomize at least 2022 F2/F3 patients to either active (1348 patients) or placebo         (674 
patients) treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 
enrolled patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 
at least 2 of the following conditions: persistent elevated (absence of normal ALT within the past year, 
obesity defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education 
Program’s Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also 
be enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of at least 2224 patients will be enrolled, including the exploratory F1 group. 
 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
 
• 
Elafibranor 120 mg 
• 
Placebo. 
 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the 
following 3 factors: 
 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 


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•
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients).
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 96 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be redefined 
according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory part of 
the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of 
events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
•
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV).
•
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1
to V7).
•
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience
an event listed in Section 2.1.2 (visits V8 to Vn).
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1)
3.6.1. 
Screening visits SV1 and SV2 
The following screening procedures will be performed for all potential patients at SV1 conducted during 
the screening period and prior to randomization: 
•
Signature of informed consent witnessed by the Investigator or designated person. Note: The
signature of the informed consent may also be performed before SV1.
•
Patient number allocation via IXRS.
•
Check medical history/demographics.
•
Check inclusion/exclusion criteria (described in Section 4).
•
Physical examination (described in Section 6.2.1).
•
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet


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and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco 
habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and  
Section 8). 
 
The Screening biological assessment (SB1 will be scheduled at SV1). 
 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an additional 
SV2 visit at least Week -4 prior to the planned Randomization V1, in order to obtain the results in time. 
 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 
6 months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart 
in order to have 2 consecutive values for DILI adjudication. 
 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing 
of HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 30, and 31 (see Section 4.2 and Section 3.11). 
 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated 
a patient number composed of 9 digits which is generated by the IXRS. 
 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 
 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 
 
A specific IXRS procedure manual will be provided to the Investigator. 


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3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to 
recommended Week -4): 
 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an additional 
SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood samples 
for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver biopsy. 
Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 6.1.1.2). 
 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call within 
1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon 
as possible. 
 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant cardiometabolic 
comorbidities, which are associated with rapid progression of the disease (listed in Section 3.1), will also 
be enrolled and followed as an exploratory group. 
 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 
 
At the end of the 72-week treatment period, a biopsy will be performed for all the patients under treatment 
in order to evaluate the effect of elafibranor on the liver histology. 


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When at least the first 1023 randomized patients (F2-F3) complete Week 72 (or discontinue early from 
the study treatment), a surrogate endpoint analysis will be performed and potentially filed for initial market 
approval under Subpart H or conditional approval, (see Section 9.8.1 for details). 
 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
 
3.7.1. 
Randomization Visit V1 (Week 0): 
 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). 
The patient will be contacted at least 1 week before each visit to be reminded of procedures and 
investigational product (IP) return. 
 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to 
any other study procedures. If the system confirms the randomization, it will provide the Investigator with 
a treatment number for the patient. 
 
The following will be performed only at V1: 
 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described  in  Section  5.1.1  and  
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12
 and APPENDIX III: Permitted/non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 


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Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.5) 
• 
Drug accountability (every visit from V2). 
 
Additional procedures to be performed at V7 are: 
 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
 
3.8. 
LONG-TERM TREATMENT PERIOD 
 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, death 
due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment 
as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 
 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint described 
in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of the study 
following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 1 
week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 


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• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described  in  Section  5.1.1  and  
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12
 and APPENDIX III: Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described 
in Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet 
and lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the Investigator may 
decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed 
for each phone visit. 
 
3.9. 
END OF STUDY TREATMENT VISIT 
 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop treatment 
and undergo an EOT Visit 30 days after the final administration of study drug. 
 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 


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other than an event listed in the primary composite endpoint for long-term efficacy described in 
Section 1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate 
efficacy outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described  in  Section  5.1.1  and  
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12
 and APPENDIX III: Permitted/non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2), 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following 
the EOT Visit and have no further follow-up, unless the patient experiences at the time of EOT visit, an 
ongoing adverse event possibly related to study treatment for which the follow-up should last until 
resolution of this adverse event. 
 


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Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological 
confirmation of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 for patients with baseline MELD score ≤12 
o 
the onset of: 
 
variceal bleed requiring hospitalization 
 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization 
 
spontaneous bacterial peritonitis 
 
ascites requiring treatment. 
 
o 
death due to any cause. 
 
3.11. OPTIONAL VISITS 
 
3.11.1. 
Retesting screening visits 
 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional testing 
is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
 


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• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to 
Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1). 
 
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
 
3.11.2. 
Unscheduled visits 
 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for safety 
reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
 
3.12. 
OFF-SITE STUDY PROCEDURES IN CASE OF CRISIS SITUATION 
 
Based on assessment of risk, and to ensure patient safety and minimize risks to trial integrity, the sponsor 
determined that the following optional off-site study procedures can be performed in case a study 
participant cannot attend an on-site visit during the COVID-19 crisis:  
 
• 
Safety assessment via phone call  
• 
Local lab assessment 
• 
Delivery of the study treatment to patient 
• 
Visit to patient’s home  
 
These options apply to all on-site study visits except for the randomization visit (Visit 1).  Visit 1 must 
occur on-site as per section 3.7.1.   
 
These solutions can be applied depending on the investigator’s judgment of each case and the patient’s 
agreement. The alternative solutions can be implemented in response to the COVID-19 crisis prior to the 
notification or submission to and approval of regulatory agencies and ethics committees. 
 
Before implementing any of these options for a patient, the site will contact the patient to check whether 
he/she agrees with the off-site procedures. 
 
The patient will be invited to attend an on-site visit to complete the study procedures as per protocol, as 
soon as the situation allows it. 
 


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In cases of any future emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure 
patient safety and minimize risks to trial integrity, after completion of a risk assessment similar measures 
could be taken. 
3.12.1. 
Safety and drug compliance procedures 
The following procedures will be performed via either a phone contact, or, if safe and possible, a direct 
visit to the patient:  
•
Check for AEs and occurrence of any clinical outcome (described in Section 6 and 
Section 8)
•
Report any change in diet and life style factors
•
Check concomitant/prior medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication)
•
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) 
since previous visit (for WOCBP only, every visit from V1)
•
Drug accountability
o
dates of any study drug interruption since the last dispensation and reason*
o
end of treatment (if applicable): date of last dose of study drug and reason*
o
end of study (if applicable) : date of end of study and reason*
•
if the reason is related to an AE, collect all required details
•
Physical examination if possible with a direct visit to the patient (described in Section 6.2.1)
•
Record vital signs and weight if possible with a direct visit to the patient (described in Section 6.2.1
and Section 6.2.3)
•
Based on the study visit period for the patient, excluding the quality of life assessment, additional
protocol related procedures of Section 3.7.2 or Section 3.8.1 may be performed if possible and if
necessary conditions are met
3.12.2. 
Local lab assessment 
The patient will be asked if he/she can access a local lab in the few days after the phone contact to obtain 
hematology, biochemistry and urinalysis testing.  
If a direct visit to the patient is safe and possible, the appropriate lab parameters corresponding to the on-
site study visit as described in Table 2 will be collected. 
3.12.3. 
Delivery of study treatment to the patient 


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P a g e 7 3  of 1 44 
T h e I X R S r e gistr ati o n will b e c o m pl et e d t o tri g g er st u d y dr u g kit assi g n m e nts, a n d t h e assi g n e d  dr u g kits 
c a n b e s hi p p e d t o t h e p ati e nt, or d eli v er e d dir e ctl y t o t h e p ati e nt b y t h e sit e st u d y st aff if s af e a n d 
p ossi bl e.  
 
As p er t h e us u al st u d y visit, t h e p ati e nt will b e i nstr u ct e d t o c o nti n u e t a ki n g t h e a v ail a bl e t a bl ets fr o m t h e 
e xisti n g kit u ntil h e/s h e r e c ei v es t h e n e w kit.  
 
T h e st u d y dr u g c o m pli a n c e a n d st u d y dr u g a c c o u nt a bilit y will b e p erf or m e d as d es cri b e d i n S e cti o n 7. 1 0  
a n d S e cti o n 7. 1 1  o n c e br o u g ht t o t h e st u d y sit e/st u d y p h ar m a c y.  
 
3. 1 2. 4.  
C o m pl eti o n of Mi s s e d St u d y Pr o c e d ur e s  
 
As s o o n as t h e sit u ati o n all o ws it, t h e sit e will s c h e d ul e t h e p ati e nt’s o n -sit e visit t o c o m pl et e t h e miss e d 
st u d y pr o c e d ur es (t h os e t h at c o ul d n ot b e p erf or m e d d uri n g t h e p h o n e c alls/ visit t o p ati e nt) as p er 
pr ot o c ol (s e e S e cti o n 3. 7. 2  or S e cti o n 3. 8. 1 ).  
 
 
3. 1 3.  E X P L O R A T O R Y / A N C I L L A R Y  S U B S T U D Y  
 
E x pl or at or y  s u bst u di es  mi g ht  b e  p erf or m e d  d uri n g  t h e st u d y i n sit es  t h at h a v e  t h e c orr es p o n di n g  c a p a bilit y. 
S p e cifi c  st u d y  d o c u m e nts  will  b e  pr e p ar e d  a n d  I nstit uti o n al  R e vi e w  B o ar d  (I R B)/I n d e p e n d e nt  Et hi cs 
C o m mitt e e (I E C) a n d a ut h orit y a p pr o v als s h all b e o bt ai n e d w h e n  a p pli c a bl e.  


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4. 
PATIENT SELECTION 
 
A patient will be eligible for the study only if all of the following criteria apply: 
 
4.1. 
INCLUSION CRITERIA 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as described 
below: 
o 
Cessation of menses for at least 12 months due to ovarian failure, 
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure 
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization. 
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 
in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have: 


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or UDCA; a stable dose from at least 6 months prior to diagnostic liver biopsy is 
required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, 
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like 
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on 
stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until 
the end of treatment. 
4.2. 
EXCLUSION CRITERIA 
 
Patients who meet any of the following criteria will be excluded from entering the study: 
 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients. 
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab 
at Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease 
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 
 
18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 
19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 


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(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
20. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
 
21. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
22. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
23. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
 
24. Positive anti-human immunodeficiency virus (HIV) antibody. 
25. AST and/or ALT >10 x upper limit of normal (ULN). 
26. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients 
are allowed into the study. 
27. INR >1.40 due to altered hepatic function. 
28. Platelet count <100,000/mm3 due to portal hypertension. 
29. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
30. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
31. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 


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5. 
TRIAL PROCEDURES
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, 
and the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle 
recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response 
will be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the study: 
•
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to
all blood sampling. As such, patients should not consume any breakfast or take any medication
(including study medication) in the morning prior the blood sampling. In case the patients do not
fast before a visit, a new appointment will be scheduled within 7 days.
•
On each study visit day, study treatment will be taken under fasting conditions after the blood
sampling (which corresponds to the day of the visit).
•
During the 48 hours preceding each study visit, patients should not perform strenuous exercise.
•
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol).
•
Alcohol consumption should be limited during the study duration and registered in the eCRF. Alcohol
consumption of more than 20 g per day for women and 30 g per day for men is considered abusive


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(see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams (0.6 
ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: Permitted/non-
permitted medication). 
 
5.1.3. 
Home pregnancy test for women of childbearing potential 
 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1). 
 
5.1.4. 
Sun exposure 
 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
 
5.2.1. 
Handling of patient withdrawal 
 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
 
5.2.2. 
Permanent discontinuations of study drug 
 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be permanently 
discontinued from the study. 
 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the Medical 
Monitor informed. If the discontinuation of study drug is due to an AE, the event should be documented 
in the eCRF. 
 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 


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Section 1.9.2) 
•
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in
a laboratory value that warrants permanent discontinuation of study drug therapy. Investigators
are advised to call the Medical Monitor prior to making such a decision
•
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of
background therapy that may put the patient at risk with continued participation
•
Non-permitted 
concomitant 
medication 
(described 
in 
Section 
7.12 
and
APPENDIX III: Permitted/non-permitted medication)
•
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree
to use a reliable method of birth control during the study will be permanently discontinued from
study drug
•
Non-compliance with the study treatment
•
Uncooperative patient
•
The patient requests to stop study drug permanently.
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit, unless the patient experiences at the time of EOT visit, an ongoing 
adverse event possibly related to study treatment for which the follow-up should last until resolution of 
this adverse event. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any 
event listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), 
whichever is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if 
the patient withdraws consent, or if enrollment in any other clinical trial involving an investigational 
product, or enrollment in any other type of medical research judged not to be scientifically or medically 
compatible with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 


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withdrew participation from the study. 
 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or 
possibly related AEs until the unresolved SAEs or possibly related AEs are judged by the Investigator to 
have stabilized. 
 
5.2.4. 
Patients lost to follow-Up 
 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-
out period. If vital status is determined, the patient will not be considered lost to follow-up. 
 
5.2.5. 
Replacement 
 
No patient replacements are permitted in this study. 
 
5.2.6. 
Premature discontinuation of the study 
 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change 
in opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the 
Sponsor. In addition, the Sponsor retains the right to discontinue development of the study treatment at 
any time. 
 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of patients, 
but intends only to exercise this right for valid scientific or administrative reasons. After such a decision, 
the Investigator must contact all participating patients within a reasonable period of time. As directed by 
the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest extent possible. 
 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
5.3. 
PATIENT RESCREENING 
 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient 
which allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-


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screening the patient will need to sign a new informed consent and will be entered as a new patient, 
with a new patient number. 


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6. ASSESSMENTS 
 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
 
6.1.1. 
Histological assessments 
 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed: 
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan 
and/or clinical and biological assessments) 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
 
6.1.1.1 
Recommendations related to liver biopsy 
 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
 
The patient’s platelet count and PT should be checked according to local hospital standards before the 
date of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they 
are in everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more 
than 4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous 
liver biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions 
are not all respected, a safer option would be to perform the liver biopsy by transjugular route, when 
available. 
 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, 
other available slides or new slides to be prepared from an available block of tissue may be requested to 
the site. 
 
6.1.1.2 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Liverpat, 28 rue de l’amiral Hamelin, 75 116 Paris– 
France) where they will be read and scored. Scores for total NAS, steatosis, ballooning, lobular inflammation, 
or portal inflammation, as well as fibrosis scores (both by NASH CRN scoring system, and NAFLD Ishak 
scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (Cerba Research: Ghent – Belgium, New York – USA, Sydney – 
Australia, or BARC: Johannesburg – South Africa) and specific analyses will be performed by another 
laboratory (GENFIT- Loos, France). 
 
A laboratory manual will be provided to each trial site. 
 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 24 hours 
after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, signed, 
and dated by the Investigator as soon as they are received. The Investigator should comment upon out 
of range parameters and assess clinical significance. 
 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting 
(to be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described 
Section 3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study 
Medical Monitors. 
 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1 
Laboratory assessments 
 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured 
at every visit as described in Table 2. 
 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
It is recommended to collect first morning urine samples for urinalysis. 
 
6.1.2.2 
Urinary pregnancy tests 
 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3). 
 
6.1.2.3 
Serology (SB1) 
 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
 
6.1.2.4 
Other parameters 
 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). 
 
6.1.3. 
Constitution of biobank 
 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
 
These samples will be destroyed 3 years after study results at the latest. 
 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
 
6.2.1. 
Physical examination 
 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 
 
6.2.2. 
Waist circumference 
 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel 
to the floor. The measurement is to be made at normal respiration. 
 
6.2.3. 
Vital signs 
 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the exception 
of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement in Humans 
and Experimental Animals” published in an American Heart Association scientific statement. 
 
6.2.3.1 
Important points for clinical blood pressure measurement 
 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 
80% of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks 
in the LTTP starting at V9, and at the EOT visit. 
 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
 
6.2.5. 
FibroScan 
 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the LTTP. 
Where possible, FibroScan must be done at the day of visit. Otherwise, it can be performed within 7 days 
around the visit date. 
 
Recommendations for ensuring a reliable examination are: 
 
• 
Patient must be fasting for at least 2 hours before the FibroScan examination 
 
• 
At least 10 consecutive and successful measurements shall be performed without changing 
probe position 
• 
InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the 
scan, to consider a FibroScan measure as reliable. If not, it is recommended to perform a few 
additional individual measures, or to restart the entire FibroScan examination 
 
6.2.6. 
Quality of life questionnaire 
 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 
 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND
 PATIENT DISCONTINUATION RULES 
 
6.3.1. 
Creatine phosphokinase 
 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, and/or 
marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 3 to 
7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 


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described in Section 5.2.2. 
 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN. 
 
6.3.2. 
Liver function monitoring 
 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see Section 
6.5). 
Criteria used for reporting a potential DILI for adjudication are given below and correspond to the criteria 
leading to permanent study drug discontinuation. 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned randomization 
visit (V1), or, using lab results from SV1 and V1 that are at least 8 weeks apart. 
 
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
 
6.3.2.1 
Monitoring of patients with normal baseline aminotransferase values 
 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 
hours If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring 
(once a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and 
schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 
hours If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin >2 ULN: permanently discontinue 
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5 (except in case of anticoagulant therapy): 
permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and 


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Section 5.2.2). 
• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash: permanently discontinue patient from study drug and schedule EOT Visit (see Section 
3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND eosinophilia (>5%) with total count > ULN: permanently discontinue 
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
 
6.3.2.2 
Monitoring of patients with increased baseline aminotransferase values 
 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases >5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently discontinue 
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5 (except in case of anticoagulant 
therapy): permanently discontinue patient from study drug and schedule EOT Visit (see Section 
3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT Visit 
(see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND eosinophilia (>5%) with total count > ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
 
6.3.3. 
Threshold for diagnosis of cirrhosis 
 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
 
A liver biopsy may be considered in order to confirm the diagnosis of cirrhosis if during a LTTP visit the 
FibroScan value is ≥ 14 kPa (with IQR/Median stiffness ratio < 30%*) associated with a platelet count 
<150 000/mm3 and at least 1 elevated serum marker of fibrosis indicative of cirrhosis (calculated NAFLD 
fibrosis >0.676 score or reported FIB-4 >2.67). 


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*InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, to consider 
a FibroScan measure as reliable. If not, it is recommended to perform a few additional individual measures, or to 
restart the entire FibroScan examination. 
 
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events. A detailed description 
of the interim analysis procedures and decision-making process will be provided in the DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 
hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 
 
6.5. 
CLINICAL EVENT COMMITTEE 
 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2), all DILI events, and all major cardiovascular events as defined 
in the CEC charter. The CEC assessment and adjudication will occur in a blinded, consistent, and unbiased 
manner throughout the course of a study to determine whether the endpoints meet the protocol-specified 
criteria. 
 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, 1 endocrinologist and 3 histopathologists, 
all of whom will be independent of the participants in the study. 
 
6.6. 
GUIDANCE FOR INVESTIGATORS 
 
6.6.1. 
Summary of safety data 
 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 completed and 5 ongoing clinical trials. A total of 659 volunteers were randomized 
in these studies performed in Phase I centers, including 561 healthy lean subjects, 60 overweight or obese 


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subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 20 with hepatic impairment 
 
(Child-Pugh class A, B or C) have been randomized to date in the completed trials. Elafibranor daily doses 
ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients suffering 
from cardiometabolic disorders and NASH. To date, 5 Phase IIa studies have been completed in which 
297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and 
safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. A Phase 2 study 
(GFT505B- 216-1) was also conducted in Primary Biliary Cholangitis (PBC) and included 45 patients with 
PBC and inadequate response to UDCA. This study evaluated the efficacy and safety of elafibranor at doses 
of 80 mg and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor daily doses 
ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months. 
 
Of the 63 Treatment emergent SAEs that have been reported cumulatively in the completed clinical 
development program, 50 occurred with elafibranor and 13 with placebo. For all SAEs, the treatment code 
has been broken (end of study unblinding). 
 
Of the 50 SAEs that occurred with elafibranor, only 10 SAEs reported in 7 subjects were considered as having 
a reasonable possibility of relationship to elafibranor by the investigators (serious adverse reaction). They 
consisted of: 
 
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years 
(in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
• 
Autoimmune hepatitis in a 56-year-old subject after 12 weeks of treatment of 120 mg 
elafibranor. The subject received her last dose of investigational product before the event. 
 
For atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease, after later investigations, 
given the medical history of the patients or the time of occurrence of the event, relationship to elafibranor 
was judged as “no reasonable possibility” by the Sponsor. 
 
All adverse reactions (adverse events reported by investigators as possibly related or related to study 
drug) reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses 
of at least 80 mg elafibranor per day are summarized in Table 3. 
 
 


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Table 3: Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed 
elafibranor clinical studies with repeated administration of elafibranor (at least 14 
days) from 80 mg/day up to 300 mg/day (MTD) 
 
System Organ Class 
Adverse Reaction 
Severity 
Number of 
cases 
(F
Gastrointestinal disorders 
Diarrhea 
Mild to 
moderat
17 (2.8%) 
Vomiting 
Mild to 
moderat
9 (1.5%) 
General disorders and 
administration site conditions 
Fatigue / Asthenia 
Mild to 
moderat
17 (2.8%) 
Investigations 
Hepatic 
enzymes 
increased 
(
i l
Mild to severe 
13 (2.1%) 
Blood creatine 
phosphokinase 
i
d
Mild to 
moderat
6 (1.0%) 
Musculoskeletal and connective 
tissue disorders 
Myalgia 
Mild to severe 
9 (1.5%) 
Metabolism and nutrition disorders 
Decreased appetite 
Mild to severe 
9 (1.5%) 
Nervous system disorders 
Dizziness 
Mild to 
moderat
6 (1.0%) 
Skin and subcutaneous tissue 
disorders 
Rash 
Mild to 
moderat
8 (1.3%) 
Renal and urinary disorders 
Renal failure/impairment Mild to 
moderat
7 (1.1%) 
 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of diarrhea, and vomiting. For general disorders, the main 
symptoms were fatigue / asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in 
biological parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine 
(reported by investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Myalgia, decrease of appetite dizziness and rash were also reported in 
more than 1% of patients but remain limited. 
 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results 
in the course of clinical trials. 
 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
 


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Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation 
Group (CTFG) document Recommendations related to contraception and pregnancy testing in clinical 
trials (September 2014)34. 
 
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with highly effective contraceptive measures throughout the study. It is recommended 
to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated 
as stated in each study protocol. 
 
6.6.2. 
Safety data conclusion 
 
Based on the cumulative experience gathered to date, gastro-intestinal disorders and asthenia / fatigue 
are considered common non-serious adverse reactions reasonably associated with elafibranor. Most of 
them are of mild to moderate intensity. Laboratory increases in serum creatinine or CPK should be 
monitored throughout clinical trials as this has been observed in Phase II trials to date, and is a known 
PPARα agonist effect. Elevation of AT will be monitored as well as DILI. In the absence of extensive human 
pregnancy data, highly effective contraception should be maintained for women of childbearing potential 
participating in clinical trials with elafibranor treatment, up to 1 month after end of study treatment. 
 
6.6.3. 
Benefit/risk assessment 
 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the 
efficacy of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, 
resolution of histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). 
While the trial was short and not designed for antifibrotic endpoints, it nonetheless showed that 
elafibranor, at 120 mg daily, improved fibrosis indirectly through the resolution of NASH. Importantly, 
elafibranor 120 mg concomitantly improved the cardiometabolic risk profile of the patients by decreasing 
plasma triglycerides, total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, 
insulin resistance, and glucose homeostasis. Together these results position elafibranor as a drug candidate 
to treat NASH with the objective to block fibrosis evolution and ultimately avoid long term liver outcomes 
while reducing cardiovascular risk. 
 
Furthermore, the Phase IIa trial in PBC subjects who had an inadequate response to UDCA demonstrated 
similar improvement in GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP 
levels was observed, resulting in significant treatment effects versus placebo on the primary endpoint, 
whilst also meeting the composite endpoint used for drug registration (i.e. serum ALP <1.67 x ULN, an 
ALP decrease >15% and total bilirubin <ULN). 


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Moreover, these studies have highlighted the good safety profile of elafibranor and no major safety 
concerns have been raised. 
 
Despite this favorable benefit-risk profile, an independent DSMB is to be established in order to review 
the safety of the treatment during the trial in an unblinded manner, to protect patient welfare and preserve 
study integrity. The safety assessments will be performed on a regular basis, every 6 months after 
Randomization of the first patient. The DSMB will consist of 5 experienced physicians (1 endocrinologist, 
1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all independent of the 
participants in the study. 
 
In addition, throughout the study, patients will benefit from close safety monitoring including assessment 
of many safety parameters and follow-up of the disease progression, mainly through noninvasive 
measures including FibroScan.


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7. 
TREATMENTS 
 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-
2- methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no 
printed inscription. The tablet contains elafibranor and inactive ingredients 
 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
 
For additional information see Investigator’s Brochure. 
 
7.2. 
PACKAGING AND LABELING 
 
7.2.1. 
Packaging 
 
Elafibranor/placebo: 
 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
 
7.2.2. 
Labeling 
 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
 
Distribution of study drug will be performed according to the Good Distribution Practices. 
 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use only” 
or other similar/appropriate statements as well as the following instructions “Please return empty packaging 
and unused products to your doctor at your next visit.” Details of carton and wallet labels are detailed in 
APPENDIX V: Product carton and wallet labeling. 
 
 
 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages (containing 
96 tablets to last approximately 3 months) allocated to the site. The pharmacy will acknowledge receipt 
of the study drug in the IXRS. 
 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and 
to the Sponsor. 
 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when applicable, 
results of any retesting performed), and if the patient fulfills all criteria to enter the treatment period, the 
Investigator will register the patient in the IXRS to randomize him/her. 
 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient 
to a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
 
A specific IXRS procedure manual will be provided to the pharmacy. 
 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the final database lock and the Sponsor authorization to unblind the trial. 
 
7.5. 
STORAGE CONDITIONS 
 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
 
7.6. 
DISPENSING OF TREATMENT 
 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to 
each site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and ensure 
the study drug is at site for the visits occurring. The IXRS will continue to project study drug requirements 
per patient until an event occurs which stops the projections for that patient. 
 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 


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package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 6 
months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and   
2 cartons with 3 wallets of 4 blisters in the LTTP. 
 
Each randomized patient will be given, from V1 and at every following visit, the study medication containing 
the adequate number of wallets to cover the drug administration for the period between visits. The time 
between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment Period 
and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond to 
the number of tablets provided to the patient at each visit. 
 
7.7. 
TREATMENT REPLACEMENT 
 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in 
case of need of treatment replacement. 
 
7.8. 
PROCEDURE FOR BLINDING 
 
The Investigator, patient, and study personnel will be blinded to the treatment. 
 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be reported 
in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned to 
active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
 
7.9. 
PROCEDURE FOR UNBLINDING 
 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will 
be stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed 
to the patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification 
number and access code. A back-up phone Interactive Response Technology (IRT) module will also be 
available should the site be unable to access the internet. The IXRS will verify the authorization to unblind 
the entered treatment carton and the screen will then display the treatment group, when completed, a 
blinded confirmatory e-mail will be sent to the Investigator and the Sponsor. 
 
The reason for unblinding should be clearly and fully documented by the Investigator. 
 
7.10. STUDY DRUG COMPLIANCE 
 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 


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If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION 
 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. 
A drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may destroy 
used and unused study drugs in accordance with the site SOP and always after the drug accountability 
has been performed by the monitor. 
 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling) 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
 
7.12. OTHER MEDICATION 
 
7.12.1. 
Handling of concomitant medication 
 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II, 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 
within 6 months prior to Screening) and information should be communicated to the Medical Monitor in order 
to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
 
7.12.2. 
Non-permitted medication  
 
The following medications are not allowed within the timeframe given in APPENDIX III: Permitted/non-
permitted medication): 


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• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 
weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
 
7.12.3. 
Permitted medication under condition  
 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician (see 
APPENDIX III: Permitted/non-permitted medication)): 
 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
 
The following medications are permitted under the condition of stable dose from at least 6 months prior 
to diagnostic liver biopsy (dose changes should be avoided up to EOT): 
 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
UDCA. 
 
 
The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
 


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Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
 
7.12.4. 
Permitted medication 
 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an “as-needed” 
basis. Patients should be discouraged from starting any new medication without consulting the 
Investigator unless the new medication is required for emergency purpose. 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
 
8.1. 
DEFINITIONS 
 
8.1.1. 
Adverse events 
 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms 
and signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-
existing condition or underlying disease; recurrence of a pre-existing condition; lack of effect, 
complication, and termination of pregnancy. 
 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, 
drug abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are 
as follows: 
 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. 
Any abnormal test result that is determined to be an error does not require reporting as an AE. 
 
An AE does not include the following: 
 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an 
AE if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 
• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 


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consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term  evaluation  (described  in  
Section 1.9.2) should not be reported as AE. 
 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is 
a treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at the 
time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
 
8.1.2. 
Adverse events of special interest (AESIs) 
 
AESIs are treatment emergent AEs corresponding to the conceptual definition of:  
 
• 
CPK elevations of severe intensity or leading to permanent study drug discontinuation 
• 
Muscle injury symptoms of severe intensity corresponding to:  
o 
Muscle pain or Myalgia 
o 
Muscle spasms or Tremor 
o 
Muscle weakness 
• 
Transaminases elevations from baseline of severe intensity or leading to permanent study drug 
discontinuation 
• 
Liver injury events of severe intensity corresponding to:  
o 
Hepatic impairment 
o 
Hepatic failure  
• 
Gastrointestinal symptoms of severe intensity corresponding to: 
o 
Abdominal pain 
o 
Constipation 
o 
Diarrhea 
o 
Nausea 
o 
Vomiting 
o 
Acute cholecystis 
o 
Acute pancreatitis 
• 
Fatigue and Asthenia of severe intensity 
• 
Serum creatinine elevations of severe intensity or leading to permanent study drug discontinuation 
• 
Renal injury events of moderate or severe intensity corresponding to: 


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o 
Renal failure 
o 
Renal impairment 
o 
Renal colic 
 
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are described 
in the section 8.6.1. 
 
 
8.1.3. 
Serious adverse events 
 
A SAE is any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.3.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.3.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.3.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see 8.1.3.1 8.1.3.4). 
 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of seriousness 
(as defined above) and considered to be possibly related (according to the Investigator) to any study-specific 
procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
 
8.1.3.1 
Life-threatening adverse events 
 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
 
8.1.3.2 
Inpatient or prolonged hospitalization 
 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 
not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 


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• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
 
8.1.3.3 
Significant or incapacitating disability 
 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
 
8.1.3.4 
Medically important conditions 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. These should usually be considered serious. 
 
Examples of such events are: 
 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
 
8.1.4. 
Clarification on serious adverse events: 
 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not 
be included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death. This does not include an 
event that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
 
8.1.5. 
Adverse drug reaction 


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An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
 
8.1.6. 
Unexpected adverse event 
 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
 
8.2. 
ASSESSMENTS 
 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
 
8.2.1. 
Intensity assessment 
 
The intensity of the AE will be graded as follows: 
 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
 
8.2.2. 
Relation to the study treatment 
 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
 
The Investigator will record the relation to the study treatment according to the following causality terms: 
 


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• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
 
8.2.3. 
Action taken and outcome 
 
The Investigator will record the action taken with drug and outcome of the event for each AE according 
to the following: 
 
Action taken with investigational drug 
 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
 
Outcome 
 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
 
8.3. 
REPORTING 


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8.3.1. 
Reporting an adverse event 
 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the Screening 
Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s medical record 
from the ICF signature until study end for each patient. Whenever possible, symptoms should be grouped 
as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal intensity, 
action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion as to whether 
there is a reasonable possibility that the AE was caused by the study drug. 
 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
 
8.3.2. 
Reporting a serious adverse event or an adverse event of special 
interest 
 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
AESI reporting starts from first study drug intake and ends at study end for each patient. 
 
Any SAE or AESI that is brought to the attention of the Investigator at any time after the reporting period 
and which is considered by him/her to be caused by the study drug within a reasonable possibility, should 
be reported. 
 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.2 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 
 
Investigators must notify, by e-mail or fax, the Sponsor designated representative
 
(LSS) Medical Affairs of all SAEs or AESIs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
 
 
 
ANY SERIOUS ADVERSE EVENTS, OR ADVERSE EVENTS OF SPECIAL INTEREST, WHETHER OR 
NOT RELATED TO THE STUDY DRUG, MUST BE REPORTED IMMEDIATELY (WITHIN 24 
HOURS) TO 
 AT THE FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 


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All SAEs or AESIs independent of the circumstances or suspected cause must be reported in ENGLISH on 
a SAE Form. The SAE/AESI Form should include a clearly written narrative describing signs, symptoms, 
intensity and treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae, in order to allow a complete medical assessment of the case and independent 
determination of the possible causality. 
 
The Investigator is also required to submit follow-up SAE/AESI reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
 
It is critical that the information provided on the initial or follow-up SAE/AESI Form matches the 
information recorded in the source documents and the eCRF for the same event. 
 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided 
reports must be anonymized. 
 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) according to 
the country-specific requirements. 
 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 
 
• 
SAEs (including events related to study procedures) 
• 
SADRs (a serious ADR) 
• 
SUSARs (Suspected unexpected serious adverse reactions) 
 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 


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Competent Authority(ies) concerned together with proposed actions. 
 
8.3.3. 
Follow-up 
 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
 
The patient must be followed up until clinical recovery is complete and laboratory results have returned 
to normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study (i.e. after EoT visit), notably for the potential related adverse events, and that 
additional investigations may be requested by the Sponsor. This information should be documented in the 
patient’s medical records. 
 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory 
abnormalities that are considered clinically relevant by the Investigator must be recorded as an AE, AESI 
or SAE as applicable. 
 
8.6. 
SPECIAL SITUATION REPORTS 
 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
 
8.6.1. 
Pregnancy 
 
In case of pregnancy a communication will be sent by the Investigator to 
 by 
faxing a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
 


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Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow reasonable 
attempts to be made to obtain information on any possible medicinal product exposure to an embryo or 
fetus and to follow up on the outcome of the pregnancy. 
 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
 
8.6.2. 
Medication error 
 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be reported 
as appropriate (see Section 8.3). 
 
8.6.3. 
Misuse 
 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as appropriate 
(see Section 8.3). 
 
8.6.4. 
Overdose 
 
This refers to the administration of a quantity of a medicinal product given per administration or cumulatively, 
which is above the maximum recommended dose according to the authorized product information (see 
Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 
 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In 
all circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before 
the first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
 
Details on the randomization process are in Section 3.2. 
 
9.2. 
ENDPOINTS 
 
9.2.1. 
Surrogate endpoint - resolution of NASH 
 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 72 weeks 
of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) and 
disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall pattern 
of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN fibrosis 
staging system and defined as progression of at least 1 stage. This surrogate endpoint will be formally 
assessed at the time of the surrogate efficacy analysis when at least the first 1023 randomized F2 and F3 
patients complete the 72 week treatment period or discontinue early from the study treatment (see 
Section 9.8.1 for details). An additional exploratory analysis of this endpoint will take place at the time of 
the final analysis. 
 
9.2.2. 
Long-term endpoint – time to clinical event/death 
 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
• 
Liver transplantation 
• 
MELD score ≥15 for patients with baseline MELD score ≤12 


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• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization, 
o 
spontaneous bacterial peritonitis,  
o 
ascites requiring treatment. 
 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 96 months after the first patient is randomized. 
 
9.2.3. 
Key Secondary Endpoints 
 
The key secondary endpoints are: 
 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
 
• 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL 
cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
 
 
These key secondary endpoints will be assessed at the time of the surrogate endpoint analysis (at least 
the first 1023 randomized patients with fibrosis stage F2 and F3) for the resolution of NASH without 
worsening of fibrosis endpoint. 
 
9.2.4. 
Other Secondary Endpoints 
 
The other secondary endpoints are: 
 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end 
of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH 
CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring 
system), or portal inflammation 


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o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 
point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and steatosis-
activity- fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis 
(SAF) scoring and with at least 1 point improvement in hepatic ballooning 
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
9.2.5. 
Exploratory endpoints 
 
The exploratory endpoint is: 
 
• 
To constitute a biobank for discovery and validation of biomarkers in 
NASH. Details on all endpoints will be given in the SAP. 


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9.3. 
ANALYSIS SETS 
 
The following analysis sets will be used in this study: 
 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main analysis 
of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all F2 and F3 patients who receive at least 1 dose of study drug. This set will be 
used to summarize safety. 
• 
Efficacy evaluable set (EES): All F2 and F3 patients in the ITT population who have taken at least 
one dose of study treatment and have a reliable liver biopsy at both baseline and at the end of 
the 72 week treatment period. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do 
not have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS. 
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients. 
• 
Full Safety Set (FSS): all r patients who receive at least 1 dose of study drug. 
 
Patients in the ITT, FITT, EES, PPS, and exploratory F1 cohorts (study population and efficacy data) will 
be analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
 
9.4.1. 
Resolution of NASH 
 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be 
tested at the two-sided 0.01 alpha level. 
 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end 
of the 72 week treatment period will be summarized by treatment group. The main analysis will be 
performed using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), 
gender (male, female), fibrosis stage (F2, F3) and baseline NAS. According to the method described in Ge 
et al. (2011)36, the statistical model will be used to estimate the difference (elafibranor/placebo) in rate 
of resolution of NASH without worsening of fibrosis and its 99% CI. The main confirmatory analysis will be 
performed when at least the first 1023 randomized F2/F3 patients have completed the 72 week treatment 
period or discontinued early from the study treatment. The main analysis will be based on the ITT. 
Supportive analysis will be based on the EES and PPS. 


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Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Supplementary analyses using multiple imputations and a pattern 
mixture model will be performed, as well as sensitivity analysis using a Cochran-Mantel-Haenszel test. 
Further details will be provided in the SAP. 
 
9.4.2. 
Long-term endpoints 
 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death will also be analyzed 
using an unadjusted Cox-proportional hazard’s model, log rank test and a nonparametric randomization 
based analysis of covariance method proposed by Saville and Koch.37 
 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median 
time to first clinical event/death and 95% confidence interval will also be presented for each treatment 
group. 
 
Missing data will be censored at the last known date. 
 
The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
 
9.5. 
OTHER STATISTICAL ANALYSIS 
 
9.5.1. 
Key secondary endpoint 
 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the 
surrogate endpoint analysis when at least the first 1023 randomized patients with fibrosis stage F2 and 
F3 have completed the 72 week treatment period or discontinued early from the study treatment. The null 
hypothesis will be tested at the two-sided 0.01 alpha level. 
 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant. A gatekeeping procedure will be constructed to control the overall Type I error rate for testing 
the key secondary efficacy endpoints at an overall two-sided alpha level of 0.01. 
 


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The main analysis will be based on the IIT. Supportive analyses will be based on the EES and PPS. 
 
9.5.2. 
Other secondary endpoints 
 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The 
main analysis will be based on the ITT. 
 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
 
Time to event endpoints such as time to first cardiovascular event/death will be analyzed using the Cox 
proportional hazard’s model in the same manner as time to clinical event/death. 
 
Continuous endpoints will be analyzed using a repeated measures Analysis of Covariance (ANCOVA) model 
with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage, baseline NAS, and time-point and 
treatment by time-point interaction. A compound symmetry covariance matrix will be used for this analysis. 
The statistical model will be used to calculate the mean treatment difference and 95% confidence interval. 
If the data does not meet the required assumptions for parametric tests, the data will be analyzed using 
a nonparametric analysis of covariance method of Zink and Koch.41 
 
Further details will be in the SAP. 
 
9.5.3. 
Subgroup analyses 
 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
• 
PNPLA3 (absence or presence of risk allele G [i.e. CC vs GG/CG], and within the at risk group, 
homozygous vs. heterozygous for the risk allel G [i.e. CG vs GG]) 
• 
Patients under statins (yes/no), defined as patients who have duration of IP exposure greater or 
equal to 60 days, with extent of exposure to statin greater than or equal to 30 days before the 
visit 7 biopsy date. 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
 
9.5.4. 
Exploratory analyses 
 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort and 


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the FITT. 
 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the primary 
endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided α=0.04 
for time to clinical event/death. 
 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant at a two-sided 1% significance level. A gatekeeping procedure will be constructed to control 
the overall Type I error rate for testing the key secondary efficacy endpoints at an overall two-sided alpha 
level of 0.01. 
 
The gatekeeping procedure will be detailed in the SAP and set up using the general method for building 
multi-stage parallel gatekeeping procedures in multiplicity problems with several families of null 
hypotheses (Dmitrienko and Tamhane, 2011, 2013).38,39 
 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected subgroups. 
In addition, different approaches will be applied for dealing with missing data. 
 
9.7. 
SAMPLE SIZE CALCULATION 
 
All sample size calculations were done in EAST 6.3. 
 
9.7.1. 
Resolution of NASH 
 
The following assumptions were made for the sample size calculation for resolution of NASH: 
 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 
 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and 
the GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 
7% response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the 
elafibranor group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response 


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rate based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate 
for patients with only stage 2 and 3 fibrosis). 
 
Based on these assumptions, a sample size of at least 1023 patients provides 90% power to show that 
elafibranor is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
 
9.7.2. 
Time to clinical event/death 
 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a conservative 
approach, no additional event rate was added for other events than histological cirrhosis or cirrhosis 
decompensation events. An annual clinical event/death rate of 7% was thus defined for the composite of 
both these endpoints. 
 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver fibrosis. 
In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an approximate 
annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 80% power 
to show that elafibranor is superior to placebo with respect to time to clinical event/death. In order to 
obtain 456 events, at least 2022 patients will be required in the IIT. 
The number of patients to be enrolled may be adjusted during the course of the study in a blinded manner 
to achieve the desired number of primary events. This will be accomplished using standard event forecasting 
methods (Anisimov, 2011).40 
 
9.8. 
SAFETY ANALYSIS 
 
Safety data (exposure, AEs, AESIs, clinical laboratory tests, vital signs, and ECGs) will be summarized by 
treatment group using descriptive statistics. The main summaries of safety will be based on the SS. 
Additional safety analysis will be based on the FSS and the exploratory F1 cohort. 
 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be summarized 


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by worst severity and relationship to study drug. AESIs, serious AEs, and AEs leading to discontinuation will 
also be summarized. Narratives will be added for all SAEs and AESIs. 
 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, 
or higher than the reference range for that parameter. The values will then be summarized using shift 
tables to evaluate categorical changes from baseline to end of the 72 week treatment period with respect 
to reference ranges. The number and percentage of patients reporting markedly abnormal clinical 
laboratory values will also be summarized by treatment group. 
 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. 
 
9.8.1. 
Surrogate endpoint analysis 
 
The analysis of resolution of NASH without worsening of fibrosis will occur when at least the first 1023 
randomized F2 and F3 patients complete 72 weeks of treatment or discontinue early from the study 
treatment. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H 
or conditional approval submission. This analysis will be done by an unblinded team separate from the 
study team; the study team will not be unblinded until the final analysis at the end of follow-up. A Data 
integrity plan will be set-up to detail the blinding/unblinding process and address how data will be 
published in view of marketing authorization and how integrity of the trial will be protected. 
 
The DSMB will periodically review safety data from the study to ensure the well-being of study participants. 
One dedicated meeting will also be held upon availability of the surrogate endpoint analysis results. 
DSMB will be provided with data summaries that will include selected efficacy results so that the DSMB 
can assess the likely benefit-risk profile of elafibranor. These are not considered a formal interim analysis, 
and no type I error adjustments will be done for these reviews. Details will be in the DSMB Charter. 
 
9.8.2. 
INTERIM ANALYSIS 
 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target 
number of primary events. Details will be in the DSMB Charter and SAP. 


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10. DATA HANDLING AND RECORD KEEPING 
 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE/AESI forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic 
data capture). Patients will not be identified by name in the eCRF or on any study documents to be 
collected by the Sponsor (or designee), but will be identified by a patient number. 
 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized person 
and explained (if necessary). All corrected data will be tracked through an audit trail. 
 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit 
dates, administration of study medication, AEs [start and stop dates] and all concomitant medications 
[start and stop dates]). All data recorded in the eCRF will be documented by source data. 
 
10.2. RETENTION OF RECORDS 
 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees 
to keep records, including the identity of all participating patients, all original signed ICFs, copies of all 
eCRFs, source documents, and detailed records of treatment disposition. 
 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, another 
institution, or to the Sponsor. 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, 
the Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for clinical 
investigators, the eCRFs and instructions for their completion and return, the procedure for obtaining 
informed consent, and the procedure for reporting AEs and SAEs/AESIs with the Investigator. In addition, 
the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable regulations 
concerning the clinical evaluation of the study drug. 
 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the Sponsor 
deems is necessary to determine that data recording and protocol adherence are satisfactory. A Study 
Monitor from 
 Late Stage Development Services will be responsible for monitoring this clinical 
trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent contact 
through verbal and written communication. The eCRFs and related source documents, as well as drug 
accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs and 
Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements 
for patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected 
to cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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All monitoring activities will be reported and archived in the Trial Master File. 
 
11.2. ETHICAL PRINCIPLES 
 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies  (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
 
This trial also complies with applicable local regulatory requirements and laws of each country in which 
the study is performed, as well as any applicable guidelines. 
 
11.3. QUALITY ASSURANCE 
 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, 
the Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable 
regulatory authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to 
his/her study records for review, being understood that these personnel will adhere to all requirements 
for patient confidentiality, and as such will not disclose any personal identity or personal medical 
information. 
 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
 
The confidentiality of the data verified and the anonymity of the patients should be respected during 
these inspections. 
 
Clinical data associates from the Sponsor’s representative will review the data for completeness and 
logical consistency. Additionally, the clinical data associates will use automated validation programs to 
help identify missing data, selected protocol violations, out of range data, and other data 
inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site 
for resolution. Clinical data associates will assure that corrections have been applied properly. 
 


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12. ETHICS AND REGULATORY 
 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be obtained 
from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in research 
studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient recruitment, and 
any other written information regarding this study to be provided to the patient or the patient’s legally 
acceptable representative must be approved by the IRB/IEC. The Sponsor will supply relevant material for 
the Investigator to submit to the IRB/IEC for the protocol’s review and approval. Verification of the IRB’s 
unconditional approval of the protocol and the written ICF statement will be transmitted to the Investigator. 
Documentation of the relevant IRB/IEC approval and of the IRB/IEC compliance with GCP guideline will 
be maintained by the site and will be available for review by the Sponsor or its designee or by the 
authorized members of regulatory agencies. 
 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a formal 
protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent protocol 
amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to the 
Investigator. 
 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing direct 
access to source data/documents. 
 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 
 
12.2. COMPETENT AUTHORITY 
 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, Amendments 
will also be submitted to CA for approval. 


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12.3. PATIENT INFORMATION AND CONSENT 
 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In accordance 
with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF approved 
by the designated IRB/IEC and will be signed and personally dated by the patient or by the patient’s 
legally acceptable representative and by the person who conducted the informed consent discussion prior 
to protocol-specific procedures being performed. A separate consent form will be obtained for optional 
genetic and biomarker samples to be stored in the blood bank. 
 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
 
12.4. PATIENT CONFIDENTIALITY 
 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by protocol 
number and patient number. 
 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
 
The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
 
12.5. DEFINITION OF THE END OF THE RESEARCH 
 
End of the research corresponds to the last observation for the last patient participating in the 
research. 


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13. FINANCING AND INSURANCE 
 
13.1. FINANCIAL ISSUES 
 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation 
of the study. 
 
13.2. INSURANCE AND PATIENT INJURY 
 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the patient’s 
medical insurance, a government program, or other responsible third party. If laws or regulations of the 
locality in which the trial is taking place require additional payment of expenses, the Sponsor shall comply 
with such law or regulation. 
 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or paraclinical 
examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
 
14.1. STUDY REPORT 
 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 Guideline 
for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality Assurance 
audit, the findings of which will be incorporated into the final version. 
 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the 
final report. 
 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential 
and shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s 
prior written consent. 
 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from 
the present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, 


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with or without comments and with or without analysis, in order to submit them to the Health Authorities 
of any country. 
 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting 
on his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their studies, 
using only clean, checked, and validated data in order to ensure the accuracy of the results. 
 
The publication of study results will be agreed between the Sponsor and the Investigators. 
 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the manuscript 
or abstract for review by the Sponsor, and, if necessary, delay publication or communication for a limited 
time in order to protect the confidentiality or proprietary nature of any information contained therein. The 
Sponsor may also request that the Sponsor’s name and/or names of one or several of its employees appear 
or not appear in such publication. 


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15. REFERENCES LIST 
 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-
845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver 
disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin 
Invest. 2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 288-
297. 
6. Poniachik J, Santibanez C, Haim D, et al. Enhancement in liver nuclear factor-kb (NF-KB) 
and activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver 
disease. The 43rd Annual Meeting of the European Association for the Study of the Liver. 
Milan, Italy, 2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and 
fatty- acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-
95. Epub 2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol.  2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha 
and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor 
necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-
2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers 
of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al. Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 


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16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces 
oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer 
cells by PPARδ ameliorates obesity induced insulin resistance. Cell Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of 
nonalcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for 
liver disease severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, 
Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology.  2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting
 clinically meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 
2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-
analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. 
J Gastroenterol.  2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol agreement and ability to predict liver-related mortality. Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology.  2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 


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management. J Hepatol. 2015;62(5):1148-1155. 
 
32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality 
risk in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. 
Clin Gastroenterol  Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available
 at: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-adjusted 
difference in proportions from clinical trials using logistic regression and weighted risk 
differences. Drug Information Journal, 45(4), 481-493. 
37. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized 
Clinical Trials Using Cox Proportional Hazards Models and Nonparametric Randomization 
Based Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
38. Dmitrienko, A., Tamhane, A.C. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011 30: 1473-1488. 
39. Dmitrienko, A., Tamhane, A.C. General theory of mixture procedures for gatekeeping. 
Biometrical Journal. 2013 55: 402-419. 
40. Anisimov, V. Predictive event modelling in multicentre clinical trials with waiting time to 
response. Pharmaceutical Statistics. 2011; 10, 517-522. 
41. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 


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16. Appendices 
 
16.1. APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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16.4. APPENDIX IV: ALCOHOL COMPARISON TABLE 
 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm).  
 
 


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16.5. APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration instructions 
X 
X 
“For Clinical Trial Use only.” 
X 
X 
“Keep out of reach of Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product and package 
return at next visit 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_000.pdf: 
Document Type:  
Document Dates: 
Study Title: 
Final Protocol(s) 
Brazil Protocol Version 3 – 27 April 2018 
Czech Republic Protocol Version 1.1 – 17 June 2016 
France Protocol Version 1.1 – 01 July 2016 
France Protocol Version 2.1 – 12 January 2017 
France Protocol Version 3.1 – 10 April 2017 
France Protocol Version 4.1 – 03 January 2020 
France Protocol Version 5.1 – 23 April 2020 
Portugal Protocol Version 1.1 – 25 July 2016 
Portugal Protocol Version 1.2 – 16 September 2016 
Sweden Protocol Version 1.1 – 29 June 2016 
UK Protocol Version 1.1 – 17 May 2016 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 
III Study to Evaluate the Efficacy and Safety of Elafibranor in 
Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Protocol Reference Number: GFT505-315-1 
NCT Number:  
NCT02704403 




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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
Protocol N°: 
 
GFT505-315-1 / EudraCT N° 2015-005385-38/ IND n°115028 
Version number: 
Amendment 2 Brazil – Final 3.0 
Release date:  
27 April 2018 
TITLE: 
RESOLVE-IT: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 
III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients with 
Nonalcoholic Steatohepatitis (NASH) and fibrosis. 
In signing below, I give agreement to the protocol. 
International Coordinators: 
 
 
________________
__ 
 
 
 
_____
_______ 
Signature 
Date (dd-mmm-yyyy) 








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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
RESOLVE-IT: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 
III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients with 
Nonalcoholic Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
Amendment 2 Brazil – Final 3.0 
DATE: 
27 April 2018 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
  
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
ePRO 
 
 
 
 
 
 
 
 
 
 
 


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AMENDMENT 2 BRAZIL: 27 APRIL 2018 
The country-specific amendment 2 for Brazil is a consequence of feedback received from the Brazilian Ethics Committee following their review of the amended 
protocol (Version 2.0, dated 10 October 2017).  
In the summary of changes tables below, added text is bolded; deleted text is struck through. 
Summary of major changes to the amended protocol 2: 
Section 
New Text 
Section 3. Trial design 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the efficacy and safety of 
elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the resolution of NASH 
without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a LTTP to assess efficacy on progression to 
cirrhosis, all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed adjudicated events 
(see Section 2.1.2). The study will terminate upon the 456th patient experiencing an event listed in the composite endpoint for long 
term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 diabetes, gender (with a 
capping of women to 40%), and fibrosis stage. 
For Brazilian patients, at the end of the 72 week period, all patients will be switched to open label LTTP with active 
drug. 
Section 3.5. Study 
periods 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week double-blind First Treatment 
Period and a LTTP up to the occurrence of a prespecified number of events. 


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Section 
New Text 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
•
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV).
•
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to V7).
•
Week 72 to end of study (EOS): LTTP with elafibranor or placebo (except for Brazil) until 456 patients experience an
event listed in Section 2.1.2 (visits V8 to Vn).
Section  3.8. 
Long-term Treatment 
Period 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, death due to any cause, or 
to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as assigned at V1 
(elafibranor 120 mg or placebo). For Brazil, the Long-term Treatment period will be open-label with all patients 
assigned to active treatment after completion of the first double-blind 72-week treatment period. 
Patients will be monitored by notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  described in Section 1.9.2 will 
result in the permanent discontinuation of study drug and discontinuation of the study following the EOT Visit (as described in 
Section 3.9 and Section 5.2.3). 
Patients will come to the site for visits every 12 weeks during the LTTP.  The procedures will be interposed every 
24 weeks, as such: 
•
LTTP visit with full procedure (Section 3.8.1)  every 24 weeks


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Section 
New Text 
•
Safety visit (Section 3.8.2) every 24 weeks
The visits will be scheduled as such : LTTP visit at 12 weeks, safety visit at 24 weeks, LTTP visit at 36 weeks, 
safety visit at 48 weeks, etc 
 The visit procedures are detailed in the following sections: 
Section  3.8.1 
Long-term Treatment 
Period Visits (V8 to Vn) 
Patients will return to the site every 12 24 weeks during the LTTP. The patient will be contacted at least 1 week before each visit 
to be reminded of procedures and IP return. 
Section  3.8.2 
Long-term Treatment 
Period intermediate 
safety visits (VI1 to VIn) 
Intermediate on-site safety visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, IP compliance control and drug 
accountability. If any information during this visit requires an additional exam, the Investigator may decide to perform an 
unscheduled visit (described in Section 3.11.2). IXRS registration will be performed for each intermediate safety visit. 
Section 6.5. Clinical event 
committee 
The CEC will conduct adjudication of all disease progression events included in the primary composite efficacy long-term endpoint 
(Section 1.9.2, except for histological cirrhosis), all DILI events, and all major cardiovascular events as defined in the CEC charter. 
The CEC assessment and adjudication will occur in a blinded, consistent, and unbiased manner throughout the course of a study to 
determine whether the endpoints meet the protocol-specified criteria.  
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist chair, all of whom will be independent of the 
participants in the study. 
Section 7.4. Method of 
assigning patient to 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug Distribution Center which 
will be responsible to send one of several blocks of treatment packages (containing 96 tablets to last approximately 3 months) 


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Section 
New Text 
treatment group 
allocated to the site. The pharmacy will acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when applicable, results of any 
retesting performed), and if the patient fulfills all criteria to enter the treatment period, the Investigator will register the patient in 
the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access code) and will ask some 
questions to check the patient eligibility. The IXRS will then allocate the patient to a treatment group (elafibranor 120 mg or 
placebo) through a patient number (with 9 digits), as described in Section 3.2. 
For Brazil, after the patient has completed the visit V7, the IXRS system will allocate all the patients to the 
elafibranor treatment group. No unblinding will be needed prior to this treatment re-allocation. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the study participants until 
the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
RESOLVE-IT: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the 
Efficacy and Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
For Brazil, the Long-term Treatment period will be open-label with all patients assigned to active treatment 
after completion of the first double-blind 72-week treatment period. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
•
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
•
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging
system and defined as progression of at least 1 stage. 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events:
•
Liver transplantation
•
MELD score ≥15
•
Hepatocellular carcinoma
•
the onset of:
o
variceal bleed,
o
hepatic encephalopathy,
o
spontaneous bacterial peritonitis,
o
ascites,
o
hepatorenal syndrome,
o
hepatopulmonary syndrome,
o
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that
these lead to hospitalization or transfusion).
Key secondary objective (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
•
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN
scoring. 


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Other secondary objectives 
•
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following
endpoints: 
o
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up
biopsy) 
o
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH
CRN scoring 
o
percentage of patients with at least 1 point improvement in histological scores (NASH CRN
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o
percentage of patients with improvement of NAS of at least 2 points.
o
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis (SAF)
activity score
o
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal
inflammation, SAF activity score
o
changes in area of fibrosis by morphometry
o
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring.
•
To assess the following endpoints at Week 72, and at the end of the LTTP:
o
changes in liver enzymes and liver markers
o
changes in noninvasive markers of fibrosis and steatosis
o
changes in lipid parameters
o
variation in body weight
o
changes in insulin resistance and glucose homeostasis markers
o
changes in inflammatory markers
o
changes in cardiovascular risk profile as assessed by Framingham scores
o
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire)
•
To assess the onset to:
o
liver cirrhosis
o
death of any cause
o
any portal hypertension or cirrhosis related events
o
cardiovascular events
o
liver-related death events.
Safety secondary objectives 
•
To assess the tolerability and safety of once a day administration of oral doses of elafibranor
120 mg: 
o
serious adverse events, adverse events, physical examination, vital signs, medical history,
electrocardiogram 
o
hematological parameters
o
liver markers
o
renal biomarkers (including urinalysis)
o
cardiac biomarkers
o
metabolic parameters
o
other biochemical safety markers.
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
•
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration
scored 0-2, and lobular inflammation scored 0-3). 
•
NAS ≥4.
•
fibrosis stage of 2 or greater and below 4, according to the NASH CRN fibrosis staging system.
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP, except for 
Brazilian patients, who will continue in an open label active LTTP Patients will be monitored by notably 


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measuring the potential appearance of cirrhosis (based on FibroScan measurement for presence of cirrhosis 
associated with biological and clinical assessments). If histological cirrhosis is confirmed as well as any 
other event listed in the long-term composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
•
674 patients in placebo group
•
1348 patients in elafibranor (GFT505) group
Number of participating centers (planned): ~280 centers 
Number of participating countries: ~26 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, 
Mexico, Colombia, Brazil, Argentina, Chile, Australia, South Africa, Puerto Rico) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
•
Screening Period: Week -12 to Week -1 prior to Randomization.
•
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or
placebo for 72 weeks.
•
Long-term Treatment Period: Week 72 to end of study (until occurrence of prespecified number of
events): extension of treatment with elafibranor (GFT505) or placebo (except for Brazil, where all
patients will be under active elafibranor treatment).
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1.
Males or females aged from 18 to 75 years inclusive at first Screening Visit.
2.
Must provide signed written informed consent and agree to comply with the study protocol.
3.
Females participating in this study must be of nonchildbearing potential or using highly efficient
contraception for the full duration of the study and for 1 month after the end of treatment, as
described below:
o
Cessation of menses for at least 12 months due to ovarian failure,
o
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented
ovarian failure
o
If requested by local IRB regulations and/or National laws, sexual abstinence may be
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of the patient)
o
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion,
vasectomized partner, or intra-uterine device)
o
-Double contraception with barrier AND highly effective hormonal method of contraception
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal
contraception associated with inhibition of ovulation; oral, injectable, or implantable
progestogen-only hormonal contraception associated with inhibition of ovulation; or
intrauterine hormone-releasing system). The hormonal contraception must be started at
least 1 month prior to Randomization.
4.
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at
least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2,
and lobular inflammation scored 0-3).
5.
NAS ≥4.
6.
Fibrosis stage of 2 or greater and below 4, according to the NASH CRN fibrosis staging system.
7.
Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
o
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy
within 6 months before Screening is available)
o
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH
o
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has
already been performed within the past year
o
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological
confirmation).
8.
If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic
liver biopsy is required.
9.
For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:


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o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, pioglitazone or insulin. Dose changes of these medications are allowed in 
the 6 months prior to diagnostic liver biopsy, except for pioglitazone and GLP-1 agonists, 
which must remain on stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of pioglitazone, GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of 
treatment (V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c 
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal 
HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
7. Weight loss of more than 5% within 6 months prior to Randomization. 
8. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
9. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
10. Pregnant or lactating females or females planning to become pregnant during the study period. 
11. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or 
positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease  
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
12. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
13. Patients who cannot be contacted in case of emergency. 
14. Known hypersensitivity to the investigation product or any of its formulation excipients. 
15. Patients with previous exposure to elafibranor. 
16. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
 
Concomitant medications: 
17. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, 
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage 
has been kept constant for at least 2 months prior to Screening. 
18. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 


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(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
19. Currently taking any medication that could interfere with study medication absorption, distribution,
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
20. Any medical conditions that may diminish life expectancy to less than 2 years including known
cancers. 
21. Evidence of any other unstable or, untreated clinically significant immunological, endocrine,
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
22. Mental instability or incompetence, such that the validity of informed consent or ability to be
compliant with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
23. Positive anti-human immunodeficiency virus antibody.
24. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN).
25. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients
are allowed into the study.
26. International normalized ratio >1.40 due to altered hepatic function.
27. Platelet count <100,000/mm3 due to portal hypertension.
28. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females.
29. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than
60 ml/min/1.73 m2).
30. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion.
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
•
liver transplantation
•
MELD score ≥15
•
HCC
•
the onset of:
o
variceal bleed
o
hepatic encephalopathy
o
spontaneous bacterial peritonitis
o
ascites
o
hepatorenal syndrome
o
hepatopulmonary syndrome
o
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that
these lead to hospitalization or transfusion).
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
Key secondary endpoint (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
Other secondary endpoints 
•
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following
parameters: 


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o
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up
biopsy)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH
CRN scoring
o
percentage of patients with at least 1 point improvement in histological scores (NASH CRN
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD
Ishak scoring system), or portal inflammation
o
percentage of patients improvement of NAS of at least 2 points
o
percentage of patients with at least a 1 point improvement in SAF activity score
o
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal
inflammation, SAF activity score
o
changes in area of fibrosis by morphometry
o
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring.
•
To assess the following endpoints at Week 72, and at the end of the LTTP:
o
changes in liver enzymes and liver markers
o
changes in noninvasive markers of fibrosis and steatosis
o
changes in lipid parameters
o
variation in body weight
o
changes in insulin resistance and glucose homeostasis markers
o
changes in inflammatory markers
o
changes in cardiovascular risk profile as assessed by Framingham scores
o
changes in quality of life (SF-36 questionnaire).
•
To assess the onset of:
o
liver cirrhosis
o
death of any cause
o
any portal hypertension or cirrhosis related events
o
cardiovascular events
o
liver-related death events.
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
•
Regulatory/ethics committee submission: January 2016
•
Initiation visits: March 2016 – March 2017
•
Recruitment period: March 2016 – March 2018
•
FPFV: March 2016
•
Surrogate endpoint analysis: Q4 2018 – Q1 2019
•
LPLV (LTTP): March 2022
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 chair, all of whom will be independent 
of the participants in the study. 








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- 
The visit SV2 only occurs if no historical biopsy within 6 months before the Screening Visit is available. A screening liver biopsy and slides shipment to the central 
pathologist must be performed at least 4 weeks before Randomization, in order to obtain the results in time. However, in some exceptional cases, the central 
reading process can be expedited allowing a shorter time between SV1 or SV2 and V1. Coagulation (platelet count and PT [INR]) should be checked locally prior to 
this liver biopsy (according to local medical standards in each hospital). 
- 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the patients 
5.
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to
Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon as possible.
6.
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient.
7.
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2.
8.
Intermediate on-site safety visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, IP compliance control and drug accountability. If any
information during this phone contact requires an additional exam, the Investigator may decide to perform an unscheduled visit.
9.
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient.
10.
In the LTTP the first ECG will be performed at V9 and then every 48 weeks thereafter.
11.
Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy.
12.
QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively),
and every 48 weeks thereafter.
13.
EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial
discontinuation).
14.
Phone visits will be performed for the follow-up of patients having permanently discontinued study drug but remaining in the study.






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Abbreviations Ab = antibody; ACR = albumin–creatinine ratio; Ag = antigen; ALT = alanine aminotransferase; Apo = apolipoprotein; AST = aspartate aminotransferase; β-NAG = 
N-acetyl-β-D-glucosaminidase; BUN = blood urea nitrogen; B = biological assessment Visit; CHI3L1 = chitinase-3-like protein 1; CK18 = cytokeratin 18; CPK = creatine phosphokinase; eGFR 
= estimated glomerular filtration rate; ELF = enhanced liver fibrosis; EOT = end of study treatment; FFA = free fatty acid; FGF = fibroblast growth factor; FIB-4 = fibrosis 4 score; FLI = 
fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; MDRD = modification of diet in renal disease; MELD = model end stage liver disease; NAFLD = 
nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen 
peptide; PT  = prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SB = Screening biological assessment Visit; SV = Screening Visit; TG = 
triglyceride; VLDL-C = very low density lipoprotein-C; V = Visit; WBC = white blood cell. 
1.
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local
laboratory. Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on
FibroScan and/or clinical or biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a
liver biopsy will be performed after approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the past year).
2.
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:
•
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.
•
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization.
•
HCV RNA can be tested, at SV1 in case of known cured hepatitis c infection, or in case of positive HCV Ab at SV1, at a retest screening visit at the latest 2 weeks prior to
the planned Randomization (V1).
3.
Dipstick at site for WOCBP only. In addition, home pregnancy tests are to be performed by WOCBP every 4 weeks from V1 (see Table 1 and Figure 2).
4.
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13).
5.
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1) are available, then
SV1 and V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits should be scheduled in order to
obtain the needed results prior to the randomization.
6.
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy.


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 2 BRAZIL: 27 APRIL 2018 ................................................................................................. 9 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 13 
TABLE OF CONTENTS ......................................................................................................................... 28 
TABLE OF TABLES .............................................................................................................................. 34 
TABLE OF FIGURES ............................................................................................................................ 35 
LIST OF ABBREVIATIONS .................................................................................................................... 36 
1.
INTRODUCTION ................................................................................................................... 39
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 39 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 39 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 41 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 42 
1.4.1. 
Pharmacology ........................................................................................................... 42 
1.4.2. 
Safety pharmacology ................................................................................................. 42 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 42 
1.4.4. 
Toxicology ................................................................................................................ 44 
1.5. 
CLINICAL STUDIES ............................................................................................................... 45 
1.5.1. 
Phase I program ........................................................................................................ 45 
1.5.2. 
Phase II program ...................................................................................................... 46 
1.6. 
CONCLUSION ....................................................................................................................... 48 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 49 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 49 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 50 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 50 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 50 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 51 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 51 
2.
TRIAL OBJECTIVES ............................................................................................................... 53
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 53 
2.1.1. 
Surrogate endpoint analysis ....................................................................................... 53 


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2.1.2. 
Long-term endpoint ................................................................................................... 53 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS .................................... 53 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 54 
2.4. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 54 
3. 
TRIAL DESIGN ..................................................................................................................... 56 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 56 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 56 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 57 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 57 
3.5. 
STUDY PERIODS .................................................................................................................. 57 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) ....................................................................... 57 
3.6.1. 
Screening visits SV1 and SV2 ..................................................................................... 57 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): ....... 59 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 59 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 59 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 60 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 60 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 61 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 62 
3.8.2. 
Long-term Treatment Period intermediate safety visits (VI1 to VIn) .............................. 63 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 63 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 64 
3.11. OPTIONAL VISITS ................................................................................................................ 65 
3.11.1. 
Retesting screening visits ........................................................................................... 65 
3.11.2. 
Unscheduled visits ..................................................................................................... 65 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 65 
4. 
PATIENT SELECTION ............................................................................................................ 66 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 66 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 67 
5. 
TRIAL PROCEDURES ............................................................................................................. 70 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 70 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 70 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ........................................................................ 70 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 71 
5.1.4. 
Sun exposure ............................................................................................................ 71 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 71 
5.2.1. 
Handling of patient withdrawal ................................................................................... 71 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 71 
5.2.3. 
Patient discontinuation from the Study ........................................................................ 72 


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5.2.4. 
Patients lost to follow-Up ........................................................................................... 73 
5.2.5. 
Replacement ............................................................................................................. 73 
5.2.6. 
Premature discontinuation of the study ....................................................................... 73 
5.3. 
PATIENT RESCREENING ....................................................................................................... 74 
6. 
ASSESSMENTS ..................................................................................................................... 75 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 75 
6.1.1. 
Histological assessments ............................................................................................ 75 
6.1.2. 
Biological assessments ............................................................................................... 76 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 77 
6.2.1. 
Physical examination.................................................................................................. 77 
6.2.2. 
Waist circumference .................................................................................................. 78 
6.2.3. 
Vital signs ................................................................................................................. 78 
6.2.4. 
Electrocardiogram...................................................................................................... 78 
6.2.5. 
FibroScan .................................................................................................................. 79 
6.2.6. 
Quality of life questionnaire ........................................................................................ 79 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 79 
6.3.1. 
Creatine phosphokinase ............................................................................................. 79 
6.3.2. 
Liver function monitoring ........................................................................................... 79 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................. 81 
6.4. 
SAFETY & EFFICACY DATA REVIEW....................................................................................... 81 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 82 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 82 
6.6.1. 
Summary of safety data ............................................................................................. 82 
6.6.2. 
Safety data conclusion ............................................................................................... 85 
6.6.3. 
Benefit/risk assessment ............................................................................................. 85 
7. 
TREATMENTS ....................................................................................................................... 87 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 87 
7.2. 
PACKAGING AND LABELING .................................................................................................. 87 
7.2.1. 
Packaging ................................................................................................................. 87 
7.2.2. 
Labeling .................................................................................................................... 87 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ......................................... 88 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 88 
7.5. 
STORAGE CONDITIONS ........................................................................................................ 88 
7.6. 
DISPENSING OF TREATMENT ................................................................................................ 88 
7.7. 
TREATMENT REPLACEMENT .................................................................................................. 89 
7.8. 
PROCEDURE FOR BLINDING ................................................................................................. 89 
7.9. 
PROCEDURE FOR UNBLINDING ............................................................................................. 89 
7.10. STUDY DRUG COMPLIANCE .................................................................................................. 90 


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7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 90 
7.12. OTHER MEDICATION ............................................................................................................ 90 
7.12.1. 
Handling of concomitant medication ........................................................................... 90 
7.12.2. 
Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) ............................................................................................................... 91 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) ......................................................................... 91 
7.12.4. 
Permitted medication ................................................................................................. 92 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 93 
8.1. 
DEFINITIONS ....................................................................................................................... 93 
8.1.1. 
Adverse events .......................................................................................................... 93 
8.1.2. 
Serious adverse events .............................................................................................. 94 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 95 
8.1.4. 
Adverse drug reaction ................................................................................................ 96 
8.1.5. 
Unexpected adverse event ......................................................................................... 96 
8.2. 
ASSESSMENTS ..................................................................................................................... 96 
8.2.1. 
Intensity assessment ................................................................................................. 96 
8.2.2. 
Relation to the study treatment .................................................................................. 97 
8.2.3. 
Action taken and outcome .......................................................................................... 97 
8.3. 
REPORTING ......................................................................................................................... 98 
8.3.1. 
Reporting an adverse event ....................................................................................... 98 
8.3.2. 
Reporting a serious adverse event .............................................................................. 98 
8.3.3. 
Follow-up ................................................................................................................ 100 
8.4. 
POST STUDY REPORTING REQUIREMENTS .......................................................................... 100 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS .............................................................................. 100 
8.6. 
SPECIAL SITUATION REPORTS ........................................................................................... 101 
8.6.1. 
Pregnancy ............................................................................................................... 101 
8.6.2. 
Medication error ...................................................................................................... 101 
8.6.3. 
Misuse .................................................................................................................... 101 
8.6.4. 
Overdose ................................................................................................................ 102 
8.6.5. 
Abuse ..................................................................................................................... 102 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ..................................................................... 103 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ............................................................... 103 
9.2. 
ENDPOINTS ....................................................................................................................... 103 
9.2.1. 
Surrogate endpoint - resolution of NASH ................................................................... 103 
9.2.2. 
Long-term endpoint – time to clinical event/death ..................................................... 103 
9.2.3. 
Key Secondary Endpoint .......................................................................................... 104 
9.2.4. 
Other Secondary Endpoints ...................................................................................... 104 


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9.3. 
ANALYSIS SETS .................................................................................................................. 105 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS.................................................................................... 106 
9.4.1. 
Resolution of NASH.................................................................................................. 106 
9.4.2. 
Long-term endpoints ............................................................................................... 106 
9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................... 107 
9.5.1. 
Key secondary endpoint ........................................................................................... 107 
9.5.2. 
Other secondary endpoints ...................................................................................... 107 
9.5.3. 
Subgroup analyses .................................................................................................. 107 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 108 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 108 
9.7.1. 
Resolution of NASH.................................................................................................. 108 
9.7.2. 
Time to clinical event/death ..................................................................................... 109 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 109 
9.8.1. 
Surrogate endpoint analysis ..................................................................................... 110 
9.9. 
INTERIM ANALYSIS ............................................................................................................ 110 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 111 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................. 111 
10.2. RETENTION OF RECORDS ................................................................................................... 111 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 113 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 113 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 114 
11.3. QUALITY ASSURANCE ......................................................................................................... 114 
12. 
ETHICS AND REGULATORY ................................................................................................. 115 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 115 
12.2. COMPETENT AUTHORITY ................................................................................................... 116 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 116 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 116 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 117 
13. 
FINANCING AND INSURANCE .............................................................................................. 118 
13.1. FINANCIAL ISSUES ............................................................................................................. 118 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 118 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 119 
14.1. STUDY REPORT .................................................................................................................. 119 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 119 
15. 
REFERENCES LIST .............................................................................................................. 121 
APPENDICES .................................................................................................................................... 124 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 125 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 133 


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APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 134 
APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 136 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 137 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
19 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
23 
Table 3: 
Overview of the common non-serious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
84 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
26 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
27 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 


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GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
MTD 
maximum tolerated dose 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 


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SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 
Lipid peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 


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proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregulation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 


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macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver.  
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 


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the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
elafibranor (GFT505) has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 


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1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 


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1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials. A total of 621 volunteers were randomized in these studies performed 
in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese subjects, and 12 patients 
with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 
volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 


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The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Study GFT505-115-12 is completed. The objective was to assess the dose linearity after single oral 
administration of 120, 180, and 240 mg of elafibranor, and the time dependency of the PK parameters 
after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 
treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 


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tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides (-20% to 
-35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, insulin-
resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic dyslipidemia). In 
addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins (ApoAI and 
ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 


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high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C, and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia, and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 
these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 


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resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Since in patients with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much 
higher than in patients with early fibrosis (F1), the population evaluated for the long-term outcome needs 
to be based on the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit 
within a reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 


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population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 
fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint).  
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 


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hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 


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An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 
will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
•
Resolution of NASH is defined as the disappearance of ballooning and disappearance or
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not
qualifying for steatohepatitis.
•
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging
system and defined as progression of at least 1 stage.
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events:
•
Liver transplantation
•
MELD score ≥15
•
HCC
•
the onset of:
o
variceal bleed
o
hepatic encephalopathy
o
spontaneous bacterial peritonitis
o
ascites
o
hepatorenal syndrome
o
hepatopulmonary syndrome
o
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that
these lead to hospitalization or transfusion).
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
•
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN
scoring.


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2.3. 
OTHER SECONDARY OBJECTIVES 
•
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following
endpoints:
o
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up
biopsy)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH
CRN scoring
o
percentage of patients with at least 1 point improvement in histological scores (NASH CRN
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD
Ishak scoring system), or portal inflammation
o
percentage of patients with improvement of NAS of at least 2 points
o
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis
(SAF) activity score
o
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal
inflammation, SAF activity score
o
changes in area of fibrosis by morphometry
o
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring.
•
To assess the following endpoints at Week 72 and at the end of the LTTP:
o
changes in liver enzymes and liver markers
o
changes in noninvasive markers of fibrosis and steatosis
o
changes in lipid parameters
o
variation in body weight
o
changes in insulin resistance and glucose homeostasis markers
o
changes in inflammatory markers
o
changes in cardiovascular risk profile as assessed by Framingham scores
o
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire).
•
To assess the onset to:
o
liver cirrhosis
o
death of any cause
o
any portal hypertension or cirrhosis related events
o
cardiovascular events
o
liver-related death events
2.4. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
•
SAE, AE, physical examination, vital signs, medical history, ECG
•
hematological parameters


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•
liver markers
•
renal biomarkers (including urinalysis)
•
cardiac biomarkers
•
metabolic parameters
•
other biochemical safety markers.


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3.
TRIAL DESIGN
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient experiencing an event listed in the composite endpoint for long term 
efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. 
For Brazilian patients, at the end of the 72 week period, all patients will be switched to open label LTTP 
with active drug. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
•
Elafibranor 120 mg
•
Placebo.
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
•
Type 2 diabetes (yes, no)
•
Gender (male, female) (with a capping of women to 40%)
•
Fibrosis stage (F2, F3).
Treatment assignments will be made using an interactive voice/web response system (IXRS). 


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3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
•
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV).
•
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to
V7).
•
Week 72 to end of study (EOS): LTTP with elafibranor or placebo (except for Brazil) until 456
patients experience an event listed in Section 2.1.2 (visits V8 to Vn).
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) 
3.6.1. 
Screening visits SV1 and SV2 
The following screening procedures will be performed for all potential patients at SV1 conducted during the 
screening period and prior to randomization: 
•
Signature of informed consent witnessed by the Investigator or designated person. Note: The
signature of the informed consent may also be performed before SV1.
•
Patient number allocation via IXRS.
•
Check medical history/demographics.
•
Check inclusion/exclusion criteria (described in Section 4).
•
Physical examination (described in Section 6.2.1).
•
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits.
•
Record vital signs (described in Section 6.2.3).
•
Record height, weight, and waist circumference.


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•
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication)
•
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit.
•
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8).
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an 
additional SV2 visit at least Week -4  prior to the planned Randomization V1, in order to obtain the results 
in time. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
•
Blood samples (described in Table 2).
•
Urinalysis dipstick.
•
Urinary pregnancy test (for women of childbearing potential only [WOCBP]).
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 
months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart in 
order to have 2 consecutive values for DILI adjudication.   
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study 
as described in exclusion criteria 5, 11, 29, and 30 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 

First 3 digits corresponding to the ISO numeric country code (this number will be predefined),

Next 3 digits corresponding to the site number (this number will be predefined),

Last 3 digits corresponding to the numerical order of the patient entry at the study site.
A specific IXRS procedure manual will be provided to the Investigator. 


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3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended 
Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an 
additional SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
•
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4.
•
Fibrosis stage 2 and 3.
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 
At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 


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When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), a surrogate endpoint 
analysis will be performed and potentially filed for initial market approval under Subpart H or conditional 
approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
•
Check inclusion/exclusion criteria (detailed in Section 4).
•
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS.
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in
Section 5.1.2), and tobacco habits
•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication)
•
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6)


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•
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8)
•
Study placebo or drug dispensation (described in Section 7.6)
•
Blood samples (described in Table 2)
•
Urinalysis and urinary dipstick (described in Table 2)
•
Urinary pregnancy test (for WOCBP only)
•
Provision of home pregnancy test kits (for WOCBP only)
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1)
•
Record waist circumference (V1, V3, V5, and V7, only)
•
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4)
•
FibroScan (V1 and V7 only, described in Section 6.2.5)
•
Drug accountability (every visit from V2).
Additional procedures to be performed at V7 are: 
•
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation.
•
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy.
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the LTTP will be the prevention of progression to 
cirrhosis, death due to any cause, or to portal hypertension/cirrhosis related events (as described in 
Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). For Brazil, the Long-term Treatment period will be open-
label with all patients assigned to active treatment after completion of the first double-blind 72-week 
treatment period. 
Patients will be monitored by notably measuring the appearance of cirrhosis (based on FibroScan 
measurement associated with biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint 
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
Patients will come to the site for visits every 12 weeks during the LTTP.  The procedures will be interposed 
every 24 weeks, as such: 


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•
LTTP visit with full procedure (Section 3.8.1)  every 24 weeks
•
Safety visit (Section 3.8.2) every 24 weeks
The visits will be scheduled as such : LTTP visit at 12 weeks, safety visit at 24 weeks, LTTP visit at 36 
weeks, safety visit at 48 weeks, etc 
 The visit procedures are detailed in the following sections: 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 
1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits
•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication)
•
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6)
•
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8)
•
Study placebo or drug dispensation (described in Section 7.6)
•
Blood samples (described in Table 2)
•
Urinalysis and urinary dipstick (described in Table 2)
•
Urinary pregnancy test (for WOCBP only)
•
Provision of home pregnancy test kits (for WOCBP only)
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1)
•
Record waist circumference
•
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4)
•
FibroScan (described in Section 6.2.5)
•
Drug accountability
•
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation
•
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy.


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3.8.2. 
Long-term Treatment Period intermediate safety visits (VI1 to VIn) 
Intermediate on-site safety visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data 
collection on diet and lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test 
results, IP compliance control and drug accountability. If any information during this visit requires an 
additional exam, the Investigator may decide to perform an unscheduled visit (described in Section 
3.11.2). IXRS registration will be performed for each intermediate safety visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits
•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication)
•
Quality of life assessment (described in Section 6.2.6)
•
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8)
•
Blood samples (described in Table 2)
•
Urinalysis and urinary dipstick (described in Table 2)
•
Urinary pregnancy test (for WOCBP only)
•
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only)


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•
Record waist circumference
•
12-lead ECG (described in Section 6.2.4)
•
Drug accountability.
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
•
IXRS registration.
•
Reporting of safety information regarding:
o
any new AEs
o
resolution of previous AEs
o
change in severity of existing AEs
o
occurrence of any cardiovascular events
o
occurrence of diabetes (for patients not previously diagnosed with diabetes)
o
worsening of diabetes (for patients previously diagnosed with diabetes).
•
Reporting of any change in diet and life style factors
•
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation
•
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation
of cirrhosis)
•
Reporting of any of the following events (primary composite endpoint for long-term efficacy
evaluation):
o
liver transplantation
o
MELD score ≥15
o
HCC
o
the onset of:

variceal bleed


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
hepatic encephalopathy

spontaneous bacterial peritonitis

ascites

hepatorenal syndrome

hepatopulmonary syndrome

chronic gastrointestinal blood loss due to portal hypertensive gastropathy
(provided that these lead to hospitalization or transfusion).
o
death due to any cause.
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
•
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.
•
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to
Randomization (V1).
•
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 


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4.
PATIENT SELECTION
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1.
Males or females aged from 18 to 75 years inclusive at first Screening Visit.
2.
Must provide signed written informed consent and agree to comply with the study protocol.
3.
Females participating in this study must be of nonchildbearing potential or using highly efficient
contraception for the full duration of the study and for 1 month after the end of treatment, as
described below:
o
Cessation of menses for at least 12 months due to ovarian failure,
o
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically
documented ovarian failure
o
If requested by local IRB regulations and/or National laws, sexual abstinence may be
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation
to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
o
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion,
vasectomized partner, or intra-uterine device)
o
Double contraception with barrier AND highly effective hormonal method of contraception
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal
contraception associated with inhibition of ovulation; oral, injectable, or implantable
progestogen-only hormonal contraception associated with inhibition of ovulation; or
intrauterine hormone-releasing system). The hormonal contraception must be started at
least 1 month prior to Randomization.
4.
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular
inflammation scored 0-3).
5.
NAS ≥4.
6.
Fibrosis stage of 2 or greater and below 4, according to the NASH CRN fibrosis staging system.
7.
Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
o
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy
within 6 months before screening is available)
o
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on
NASH


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o
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy
has already been performed within the past year
o
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological
confirmation.
8.
If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic
liver biopsy is required.
9.
For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:
o
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e.,
implementation of a new anti-diabetic therapy) for patients treated with metformin,
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like
peptide (GLP)-1 agonists, pioglitazone or insulin. Dose changes of these medications are
allowed in the 6 months prior to diagnostic liver biopsy, except for pioglitazone and GLP-1
agonists, which must remain on stable dose in the 6 months prior to diagnostic liver
biopsy.
o
no implementation of pioglitazone, GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of
treatment (V7).
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1.
Known chronic heart failure (Grade I to IV of New York Heart Association classification).
2.
History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in
the course of the study.
3.
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.
4.
Type 1 diabetes patients.
5.
Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%)
leads to exclusion.
6.
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial
infarction, revascularization procedures).
7.
Weight loss of more than 5% within 6 months prior to Randomization.
8.
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably,
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are
excluded.


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9.
Current or recent history (<5 years) of significant alcohol consumption. For men, significant
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table.
10. Pregnant or lactating females or females planning to become pregnant during the study period.
11. Other well documented causes of chronic liver disease according to standard diagnostic procedures
including, but not restricted to:
o
Positive hepatitis B surface antigen (HBsAg)
o
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at
Screening)
o
Suspicion of drug-induced liver disease
o
Alcoholic liver disease
o
Autoimmune hepatitis
o
Wilson’s disease
o
Primary biliary cirrhosis, primary sclerosing cholangitis
o
Genetic homozygous hemochromatosis
o
Known or suspected HCC
o
History or planned liver transplant, or current MELD score >12.
12. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the
recommendations of National Law in force applicable to clinical trials.
13. Patients who cannot be contacted in case of emergency.
14. Known hypersensitivity to the investigation product or any of its formulation excipients.
15. Patients with previous exposure to elafibranor.
16. Patients who are currently participating in, plan to participate in, or have participated in an
investigational drug trial or medical device trial containing active substance within 30 days or five
half-lives, whichever is longer, prior to Screening.
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 
17. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe,
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept
constant for at least 2 months prior to Screening.
18. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to:
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to
Screening and up to end of treatment.
19. Currently taking any medication that could interfere with study medication absorption, distribution,
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g.,
indomethacin, which are not permitted from Randomization until end of treatment.
Associated illnesses or conditions: 


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20. Any medical conditions that may diminish life expectancy to less than 2 years including known
cancers.
21. Evidence of any other unstable or, untreated clinically significant immunological, endocrine,
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease
22. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant
with the study is uncertain.
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
23. Positive anti-human immunodeficiency virus (HIV) antibody.
24. AST and/or ALT >10 x upper limit of normal (ULN).
25. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are
allowed into the study.
26. INR >1.40 due to altered hepatic function.
27. Platelet count <100,000/mm3 due to portal hypertension.
28. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females.
29. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2).
30. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the
measurement can be repeated prior to Randomization. In this case, retest should be performed within
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion.


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5.
TRIAL PROCEDURES
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 
2, Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations 
for 
the 
TLC 
diet 
are 
detailed 
in 
APPENDIX II: 
Adequate 
diet 
and 
lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
•
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all
blood sampling. As such, patients should not consume any breakfast or take any medication
(including study medication) in the morning prior the blood sampling. In case the patients do not
fast before a visit, a new appointment will be scheduled within 7 days.
•
On each study visit day, study treatment will be taken under fasting conditions after the blood
sampling (which corresponds to the day of the visit).
•
During the 48 hours preceding each study visit, patients should not perform strenuous exercise.
•
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol).


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•
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in:
o
12-ounces/350 ml of beer (5% alcohol content)
o
5-ounces/150 ml of wine (12% alcohol content)
o
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka,
whiskey).
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1) 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 


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Some possible reasons that may lead to permanent early study drug discontinuation include: 
•
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2)
•
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are
advised to call the Medical Monitor prior to making such a decision
•
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of
background therapy that may put the patient at risk with continued participation
•
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication)
•
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug
•
Non-compliance with the study treatment
•
Uncooperative patient
•
The patient requests to stop study drug permanently.
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 


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and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 


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5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 
the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed: 
•
At baseline
•
After 72 weeks of treatment
•
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the
previous year.
•
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or
clinical and biological assessments)
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
•
Needle core biopsy
•
Biopsy obtained with a 16 or lower gauge needle
•
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length
•
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe
biopsy should be used for future biopsies.
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent, via the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – 
Australia, or Johannesburg – South Africa), to the central pathologist where they will be read and scored. 
Scores for total NAS, steatosis, ballooning, lobular inflammation, or portal inflammation, as well as fibrosis 
scores (both by NASH CRN scoring system, and NAFLD Ishak scoring system) and fibrosis area by 
morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 
24 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, 
signed, and dated by the Investigator as soon as they are received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 
3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3).  
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
•
HIV ab I/II
•
HBsAg
•
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1])
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 


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6.2.2. 
Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel to 
the floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
•
The patient should be seated comfortably with the back supported and the upper arm bare without
constrictive clothing. The legs should not be crossed.
•
The arm should be supported at heart level, and the bladder of the cuff should encircle at least
80% of the arm circumference.
•
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and
the first and last audible sounds should be taken as systolic and diastolic pressure. The column
should be read to the nearest 2 mmHg.
•
Neither the patient nor the observer should talk during the measurement.
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 
6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 


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6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the 
LTTP under 2 hour fasting conditions. Where possible, FibroScan must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.  
In case of result ≥14 kPa or of sudden increase from previous measurement, a repeated measurement will 
be required 4 weeks later (to be performed at an unscheduled visit). 
If at baseline, the measurement gives a value ≥14 kPa but without being associated with confirmed 
histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but will not be 
used for the detection of cirrhosis (no repeat test required for patients with baseline≥14 kPa at V1). 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION 
RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 
3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN.  
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 


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For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned 
randomization visit (V1), or, using lab results from SV1 and  V1 that are at least 8 weeks apart.  
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
•
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment
schedule
•
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours
If during the following retest:
o
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once
a week)
o
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >5 x ULN: retest after 48 to 72 hours
If during the following retest:
o
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2)
o
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week).
•
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x ULN AND increase in INR>1.5: permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study drug and 
schedule EOT Visit (see Section 3.9 and Section 5.2.2).
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
•
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per
assessment schedule
•
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours


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o
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial
monitoring (once a week)
o
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3 x baseline value AND increase in INR>1.5: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
•
Increase in AT >3x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2).
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 12 weeks at each visit in the LTTP. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (calculated NAFLD fibrosis >0.676 score or reported FIB-4 >2.67). 
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. A 
detailed description of the interim analysis procedures and decision-making process will be provided in the 
DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 
1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 


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6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 chair, all of whom will be independent 
of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 clinical trials. A total of 621 volunteers were randomized in these studies performed 
in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese subjects, and 12 patients 
with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety 
of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 69 SAEs that have been reported cumulatively in the completed clinical development program, 
48 occurred with elafibranor, 13 with placebo, and 8 prior to administration of study medication. For all 
SAEs, the treatment code has been broken (end of study unblinding). 
Of the 48 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the investigators (serious adverse reaction). They consisted of:  
•
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary
disease treated with elafibranor 80 mg
•
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug
administration of elafibranor 80 mg
•
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg
•
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg
•
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor
120 mg.


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•
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease).
For 3 of the cases (atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease) after 
later investigations, given the medical history of the patients or the time of occurrence of the event, 
relationship to elafibranor was judged as “no reasonable possibility” by the Sponsor. 
For all completed studies to date with repeated administration of elafibranor (at least 14 days) from 
80 mg/day up to 300 mg/day (maximum tolerated dose [MTD]), numbers and percentages of frequency of 
non-serious adverse drug reactions (AEs reported by investigators as possibly related or related to study 
drug) have been calculated compared to the total number of subjects treated with elafibranor and the total 
number of subjects treated with placebo. 
Only non-serious adverse reactions with frequency >1% are considered for reporting. Given the small 
numbers for each adverse reaction identified with a frequency >1%, an imbalance in frequency of 
occurrence compared to placebo is reported when the relative delta is ≥30%. 
The common non-serious adverse drug reactions reported with repeated doses of at least 80 
mg elafibranor per day are summarized in Table 3. 


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Table 3: 
Overview of the common non-serious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
System Organ Class 
Adverse Reaction 
Severity 
Number of cases 
(Frequency %) 
Gastrointestinal disorders 
Diarrhea 
Mild to moderate 
17 (2.9%) 
Vomiting 
Mild to moderate 
9 (1.5%) 
General disorders and administration site 
conditions 
Fatigue / Asthenia 
Mild to moderate 
17 (2.9%) 
Investigations 
Hepatic enzymes increased (mainly 
transaminases) 
Mild to severe 
11 (1.9%) 
Blood creatine phosphokinase increased 
Mild to moderate 
6 (1.0%) 
Musculoskeletal and connective tissue 
disorders 
Myalgia 
Mild to severe 
9 (1.5%) 
Metabolism & nutrition disorders 
Decrease appetite 
Mild to severe 
9 (1.5%) 
Skin and subcutaneous tissue disorders 
Rash 
Mild to moderate 
8 (1.4%) 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 
7 (1.2%) 
Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of diarrhea and vomiting. For general disorders, the main 
symptoms were fatigue / asthenia. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Myalgia, decrease of appetite and rash were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 


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teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014)34.  
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol. In the absence of a clinical PK interaction study between elafibranor and 
contraceptive steroids, the exclusive use of hormonal contraceptive methods during clinical trials should be 
avoided, and they should be accompanied by barrier methods. 
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as diarrhea and 
vomiting, and asthenia or fatigue are considered common adverse reactions reasonably associated with 
elafibranor. Most of them are of mild to moderate intensity. As previously, laboratory increases of serum 
creatinine or CPK should be monitored throughout clinical trials as this has been observed in Phase II trials, 
and is a known PPARα agonist effect. Elevation of AT will be monitored as well as DILI. In the absence of 
human pregnancy data, double contraception should be maintained for women of childbearing potential 
participating in clinical trials with elafibranor treatment, up to 1 month after end of study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 
objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent DSMB is to be established in order to review the 
safety of the treatment during the trial in an unblinded manner, to protect patient welfare and preserve 
study integrity. The safety assessments will be performed on a regular basis, every 6 months after 


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Randomization of the first patient. The DSMB will consist of 5 experienced physicians (1 endocrinologist, 1 
cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all independent of the 
participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 


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7.
TREATMENTS
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: Product carton and wallet labeling 
. 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
For Brazil, after the patient has completed the visit V7, the IXRS system will allocate all the patients to the 
elafibranor treatment group. No unblinding will be needed prior to this treatment re-allocation. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and 


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ensure the study drug is at site for the visits occurring. The IXRS will continue to project study drug 
requirements per patient until an event occurs which stops the projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) which correspond to the 
number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number 
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available 
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the 
entered treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II, 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 
within 6 months prior to Screening) and information should be communicated to the Medical Monitor in 
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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
•
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling)
•
Quantity destroyed
•
Method of destruction
•
Person who disposed the drug.
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 


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order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” 
basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I, 
APPENDIX 
III: 
Permitted/non-permitted medication) 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 
weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
pioglitazone 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
Ursodeoxycholic acid. 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
pioglitazone 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for pioglitazone and GLP-1 agonists, which must 
be on stable dose in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of pioglitazone, SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 
months prior to the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE.  
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 


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not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 


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• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 


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• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 


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Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient. Whenever possible, symptoms 
should be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, 
maximal intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F2, F3) 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) 
and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall 
pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN 
fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the surrogate efficacy analysis when at least 1023 patients complete the 
72 week treatment period or discontinue early from the study (see Section 9.8.1 for details). An additional 
exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 


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• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the surrogate endpoint analysis (at least 
1023 patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 


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• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
 
Patients in the ITT, FITT, and PPS (study population and efficacy data) will be analyzed based on 
randomized treatment. Patients in the SS and FSS (safety data) will be analyzed based on actual treatment 
received. 


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9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 99% confidence interval. The main confirmatory analysis will be performed 
when at least 1023 F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death and time to first 
cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s model, log 
rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 


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9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the 
surrogate endpoint analysis when at least 1023 of patients with fibrosis stage F2 and F3 have completed 
the 72 week treatment period or discontinued from the study. The null hypothesis will be tested at the 
two-sided 0.01 alpha level. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 
data will be analyzed using a nonparametric analysis of covariance method of Zink and Koch.37 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 


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• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the 
primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided 
α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.01. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 


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response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 


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summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics.  
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when 1023 F2 and F3 patients 
complete 72 weeks of treatment or discontinue early from the study. The null hypothesis will be tested at 
the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The DSMB will review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. Details 
will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 


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12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 
 
 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1.1 Czech Republic 
DATE: 
June 17, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
 
 
 
 
.com 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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AMENDMENT 1.1 – CZECH REPUBLIC: 17 JUNE 2016 
Amendment 1.1 - Czech Republic addresses the grounds for non-acceptance from the State Institute for 
Drug Control dated 10 June 2016. 
A single revision was made to protocol section noted below as well as to the study synopsis. Added text is 
bolded; deleted text is struck through. 
Summary of the major change to the protocol: 
Section 
New Text 
4.1 
Inclusion 
Criteria 
Original text 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 
g/day), or ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy. 
New text 
9. 
If a patient is treated by one of the following drugs (vitamin E 
(>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or ursodeoxycholic acid), 
stable dose from at least 6 months prior to diagnostic liver biopsy is required. 
 
Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 
 
The version number and date were updated throughout the protocol 
 
Typographical errors and formatting were corrected throughout the protocol. 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Exploratory objectives 
 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 


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o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
 
Safety secondary objectives 
 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
 
NAS ≥4. 
 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine aminotransferase 
(ALT), obesity defined by a body mass index (BMI) 30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
 
674 patients in placebo group 
 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
 
Screening Period: Week-12 to Week -1 prior to Randomization. 
 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Body Mass Index ≤45 kg/m². 


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4. Females participating in the study must either not be of childbearing potential (hysterectomy, 
bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation 
of menses for at least 12 months due to ovarian failure) or using efficient double contraception: 
hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device, or other 
mechanical contraception method + condom or diaphragm or spermicide for the full duration of the 
study and for 1 month after the end of treatment. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. If a patient is treated by one of the following drugs (vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid), stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in antidiabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e., implementation of a new antidiabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfamides, or insulin. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients. 
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol Consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 


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o 
positive hepatitis C Virus RNA) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
25. Positive anti-human immunodeficiency virus antibody. 
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. International normalized ratio >1.4. 
29. platelet count <100,000/mm3. 
30. Serum creatinine levels >135 µmol/L (>1.53 mg/dL) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 
repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 


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Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
 
liver transplantation 
 
MELD score ≥15 
 
HCC 
 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 


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Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
 
Regulatory/ethics committee submission: January 2016 
 
Initiation visits: February 2016 – March 2017 
 
Recruitment period: February 2016 – December 2017 
 
FPFV: February 2016 
 
Interim analysis : August – October 2018 
 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction, and stroke events as 
defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 








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8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
10. ECG will be performed every 48 weeks starting at V9. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 






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= fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; 
NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing protein 3; PT  = 
prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = triglyceride; VLDL-C 
= very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:  
 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 1.1 – CZECH REPUBLIC: 17 JUNE 2016 ............................................................................. 9 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 10 
TABLE OF CONTENTS ......................................................................................................................... 25 
TABLE OF TABLES .............................................................................................................................. 30 
TABLE OF FIGURES ............................................................................................................................ 31 
LIST OF ABBREVIATIONS .................................................................................................................... 32 
1. 
INTRODUCTION ................................................................................................................... 35 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 35 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 35 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 37 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 38 
1.4.1. 
Pharmacology ........................................................................................................... 38 
1.4.2. 
Safety pharmacology ................................................................................................. 39 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 39 
1.4.4. 
Toxicology ................................................................................................................ 40 
1.5. 
CLINICAL STUDIES ............................................................................................................... 41 
1.5.1. 
Phase I program ........................................................................................................ 41 
1.5.2. 
Phase II program ...................................................................................................... 42 
1.6. 
CONCLUSION ....................................................................................................................... 45 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 45 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 46 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 46 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 46 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 47 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 47 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 48 
2. 
TRIAL OBJECTIVES ............................................................................................................... 50 
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 50 
2.1.1. 
Surrogate endpoint -Interim analysis .......................................................................... 50 
2.1.2. 
Long-term endpoint ................................................................................................... 50 


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2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ............................................................... 50 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 51 
2.4. 
EXPLORATORY OBJECTIVES.................................................................................................. 51 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .......................................................................... 52 
2.6. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 52 
3. 
TRIAL DESIGN ..................................................................................................................... 54 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 54 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 54 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 55 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 55 
3.5. 
STUDY PERIODS .................................................................................................................. 55 
3.6. 
SCREENING PERIOD ............................................................................................................. 55 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .............. 55 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 57 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 57 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 57 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 58 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 58 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 59 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 59 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ................................................ 60 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 60 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 61 
3.11. OPTIONAL VISITS ................................................................................................................ 63 
3.11.1. 
Retesting screening visits ........................................................................................... 63 
3.11.2. 
Unscheduled visits ..................................................................................................... 63 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 63 
4. 
PATIENT SELECTION ............................................................................................................ 64 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 64 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 65 
5. 
TRIAL PROCEDURES ............................................................................................................. 68 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 68 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 68 
5.1.2. 
Dietary and fluid restrictions ....................................................................................... 68 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 69 
5.2.1. 
Handling of patient withdrawal ................................................................................... 69 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 69 
5.2.3. 
Patient discontinuation from the Study ........................................................................ 70 
5.2.4. 
Patients lost to follow-Up ........................................................................................... 71 


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5.2.5. 
Replacement ............................................................................................................. 71 
5.2.6. 
Premature discontinuation of the study ....................................................................... 71 
6. 
ASSESSMENTS ..................................................................................................................... 72 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 72 
6.1.1. 
Histological assessments ............................................................................................ 72 
6.1.2. 
Biological assessments ............................................................................................... 73 
6.1.3. 
Constitution of biobank .............................................................................................. 74 
6.1.4. 
Pharmacokinetics evaluation ...................................................................................... 74 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 75 
6.2.1. 
Physical examination.................................................................................................. 75 
6.2.2. 
Vital signs ................................................................................................................. 75 
6.2.3. 
Electrocardiogram...................................................................................................... 76 
6.2.4. 
FibroScan .................................................................................................................. 76 
6.2.5. 
Quality of life questionnaire ........................................................................................ 77 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 77 
6.3.1. 
Creatine phosphokinase ............................................................................................. 77 
6.3.2. 
Liver function monitoring ........................................................................................... 77 
6.3.3. 
Threshold for diagnostic of cirrhosis ............................................................................ 79 
6.4. 
SAFETY DATA REVIEW ......................................................................................................... 79 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 79 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 80 
7. 
TREATMENTS ....................................................................................................................... 83 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 83 
7.2. 
PACKAGING AND LABELING .................................................................................................. 83 
7.2.1. 
Packaging ................................................................................................................. 83 
7.2.2. 
Labeling .................................................................................................................... 83 
7.2.3. 
Dosage and administration of Elafibranor and placebo ................................................. 84 
7.2.4. 
Prior and concomitant medications ............................................................................. 84 
7.3. 
STORAGE CONDITIONS ........................................................................................................ 84 
7.4. 
DISPENSING OF TREATMENT ................................................................................................ 84 
7.5. 
TREATMENT REPLACEMENT .................................................................................................. 85 
7.6. 
PROCEDURE FOR BLINDING ................................................................................................. 85 
7.7. 
PROCEDURE FOR UNBLINDING ............................................................................................. 85 
7.8. 
STUDY DRUG COMPLIANCE .................................................................................................. 86 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 86 
7.10. OTHER MEDICATION ............................................................................................................ 86 
7.10.1. 
Handling of concomitant medication ........................................................................... 86 
7.10.2. 
Non-permitted medication .......................................................................................... 87 


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7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) ............................................................................................................... 87 
7.10.4. 
Permitted medication ................................................................................................. 88 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 89 
8.1. 
DEFINITIONS ....................................................................................................................... 89 
8.1.1. 
Adverse event ........................................................................................................... 89 
8.1.2. 
Serious adverse events .............................................................................................. 90 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 91 
8.1.4. 
Adverse drug reaction ................................................................................................ 92 
8.1.5. 
Unexpected adverse event ......................................................................................... 92 
8.2. 
ASSESSMENTS ..................................................................................................................... 92 
8.2.1. 
Intensity assessment ................................................................................................. 92 
8.2.2. 
Relation to the study treatment .................................................................................. 93 
8.2.3. 
Action taken and outcome .......................................................................................... 93 
8.3. 
REPORTING ......................................................................................................................... 94 
8.3.1. 
Reporting an adverse event ....................................................................................... 94 
8.3.2. 
Reporting a serious adverse event .............................................................................. 94 
8.3.3. 
Follow-up .................................................................................................................. 96 
8.4. 
POST STUDY REPORTING REQUIREMENTS ............................................................................ 96 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ................................................................................ 96 
8.6. 
SPECIAL SITUATION REPORTS ............................................................................................. 97 
8.6.1. 
Pregnancy ................................................................................................................. 97 
8.6.2. 
Medication error ........................................................................................................ 97 
8.6.3. 
Misuse ...................................................................................................................... 97 
8.6.4. 
Overdose .................................................................................................................. 98 
8.6.5. 
Abuse ....................................................................................................................... 98 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ....................................................................... 99 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ................................................................. 99 
9.2. 
ENDPOINTS ......................................................................................................................... 99 
9.2.1. 
Surrogate endpoint - resolution of NASH ..................................................................... 99 
9.2.2. 
Long-term endpoint – time to clinical event/death ....................................................... 99 
9.2.3. 
Key secondary endpoint ........................................................................................... 100 
9.2.4. 
Other secondary endpoints ...................................................................................... 100 
9.2.5. 
Exploratory endpoints .............................................................................................. 101 
9.3. 
ANALYSIS SETS .................................................................................................................. 101 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS.................................................................................... 102 
9.4.1. 
Resolution of NASH.................................................................................................. 102 
9.4.2. 
Long-term endpoints ............................................................................................... 102 


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9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................... 103 
9.5.1. 
Key secondary endpoint ........................................................................................... 103 
9.5.2. 
Other secondary endpoints ...................................................................................... 103 
9.5.3. 
Subgroup analyses .................................................................................................. 104 
9.5.4. 
Exploratory analyses ................................................................................................ 104 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 104 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 105 
9.7.1. 
Resolution of NASH.................................................................................................. 105 
9.7.2. 
Time to clinical event/death ..................................................................................... 105 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 106 
9.8.1. 
Interim analysis ....................................................................................................... 106 
9.9. 
BLINDED REASSESSMENT ................................................................................................... 107 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 108 
10.1. CRF AND SOURCE DOCUMENTS .......................................................................................... 108 
10.2. RETENTION OF RECORDS ................................................................................................... 108 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 110 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 110 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 111 
11.3. QUALITY ASSURANCE ......................................................................................................... 111 
12. 
ETHICS AND REGULATORY ................................................................................................. 112 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 112 
12.2. COMPETENT AUTHORITY ................................................................................................... 113 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 113 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 113 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 114 
13. 
FINANCING AND INSURANCE .............................................................................................. 115 
13.1. FINANCIAL ISSUES ............................................................................................................. 115 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 115 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 116 
14.1. STUDY REPORT .................................................................................................................. 116 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 116 
15. 
REFERENCES LIST .............................................................................................................. 118 
APPENDICES .................................................................................................................................... 121 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 122 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 131 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 132 
APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 134 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 135 


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 Table of Tables 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 17 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 21 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 77 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 81 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
24 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 


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HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNF 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 


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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)/ modulators with preferential activity on PPAR over 
PPAR (about fivefold more potent on human PPAR [hPPAR] than on hPPAR). The PPAR properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPAR 
response) and human hepatocytes (a mixed PPAR/ response). 
The PPAR receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPAR activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPAR compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPAR appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPAR agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPAR ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNF, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPAR knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNF, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPAR knockouts. 
Finally, in a short clinical trial, a pure PPAR agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing GT.16 


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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPAR 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPAR encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPAR and PPAR in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPAR-dependent and PPAR-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPAR reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPAR -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPAR 


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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPAR reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 


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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPAR-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPAR-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 


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1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor  has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 


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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 


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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 


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(-20% to -35%), reduction in low-density lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 


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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), Phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 


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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 


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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 


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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 


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 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
 
SAE, AE, physical examination, vital signs, medical history, ECG 
 
hematological parameters 
 
liver function parameters 
 
renal function parameters (including urinalysis) 


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 
cardiac function parameters 
 
metabolic parameters 
 
other biochemical safety markers. 
 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long-term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
 
Elafibranor 120 mg 
 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 


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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
 
Signature of informed consent witnessed by the Investigator or designated person. 
 
Patient number allocation via IXRS. 
 
Check medical history/demographics. 
 
Check inclusion/exclusion criteria (described in Section 4). 
 
Physical examination (described in Section 6.2.1). 


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 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
 
Record vital signs (described in Section 6.2.2). 
 
Record height, weight, and waist circumference. 
 
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10 
and APPENDIX III: Permitted/Non-permitted medication) 
 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1. 
 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
 
Blood samples (described in Table 2). 
 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
 
Urinalysis dipstick. 
 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 31, 
and 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 2 digits corresponding to the site number (this number will be predefined), 
 Last 2 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
 
Check inclusion/exclusion criteria (detailed in Section 4). 
 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 


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 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference (V1, V3, V5, and V7, only). 
 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 


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The following procedures will be performed at each visit from V8 to Vn: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
 
FibroScan (described in Section 6.2.4) 
 
Drug accountability 
 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety and IP compliance control. If any information during this phone contact requires a visit, 
the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS 
registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 


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All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, and Figure 1. 
The following procedures will be performed at the EOT Visit: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (described in Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (described in Section 6.2.3) 
 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 


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including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
 
IXRS registration. 
 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
 
Reporting of any change in diet and life style factors 
 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 


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3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization. 
 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1). 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the Screening Period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral 
oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses 
for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal 
contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical 
contraception method + condom or diaphragm or spermicide for the full duration of the study and for 
1 month after the end of treatment. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 
treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
If a patient is treated by one of the following drugs (vitamin E (>400 IU/day), polyunsaturated fatty 
acids (PUFAs, >2 g/day), or ursodeoxycholic acid), stable dose from at least 6 months prior to 
diagnostic liver biopsy is required. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions: 
 
No change in dose for patients treated by GLP-1 agonists 


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 
No qualitative change (i.e., implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfamides, or insulin. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients. 
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
 
Positive hepatitis B surface antigen (HBsAg) 
 
HCV RNA 
 
Suspicion of drug-induced liver disease 
 
Alcoholic liver disease 
 
Autoimmune hepatitis 


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 
Wilson’s disease hemochromatosis 
 
Primary biliary cirrhosis, primary sclerosing cholangitis 
 
Genetic hemochromatosis 
 
Known or suspected HCC 
 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
25. Positive anti-human immunodeficiency virus (HIV) antibody. 


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26. AST and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. INR >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, and 
Figure 1) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 


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 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 


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 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
 
Non-compliance with the study treatment 
 
Uncooperative patient 
 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 


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5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
 
Needle core biopsy 
 
Biopsy obtained with a 16 or lower gage needle 
 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 


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The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
 
HIV ab I/II 
 
HBsAg 
 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
 
To discover or validate biomarkers in NASH and related diseases. 
 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 


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Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 


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6.2.2.1. 
Important points for clinical blood pressure measurement: 
 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT Visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 


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Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e., ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT Visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 
must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 


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For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 


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 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the 
Long-term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or ascites, 
then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will have to be 
adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e., cardiovascular death, nonfatal myocardial, infarction, and stroke 
events as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, 
consistent, and unbiased manner throughout the course of a study to determine whether the endpoints 
meet the protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 


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6.6. 
GUIDANCE FOR INVESTIGATORS 
The safety and tolerability of GFT505 were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. 
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 


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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by Investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that Investigators review these lab results in 
the course of clinical trials. 


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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, GFT505 may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014). 
As such, all clinical trials with GFT505 including women of childbearing potential request a negative 
pregnancy test before Randomization, with effective contraceptive measures throughout the study. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between GFT505 and contraceptive steroids, the exclusive use of hormonal contraceptive methods during 
clinical trials should be avoided, and they should be accompanied by barrier methods. 
Conclusion 
Based on the cumulative experience gathered to date, gastrointestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with GFT505. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in Phase II trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
GFT505 treatment, up to 1 month after end of study treatment. 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 


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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 


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value defined in the supply strategy. Following Randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 


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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
 
Blister identification 
 
Quantity destroyed 
 
Method of destruction 
 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 


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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
 
Glitazones (pioglitazone & rosiglitazone) 
 
Fibrates 
 
Corticosteroids (parenteral & oral chronic administration only) 
 
Amiodarone 
 
Tamoxifen 
 
Methotrexate 
 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 


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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfamides 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfamides and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
 
Test result is associated with accompanying symptoms 
 
Test result requires additional diagnostic testing or medical/surgical intervention 
 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
 
Overdose without clinical sequelae 


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 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
 
Uncomplicated pregnancy 
 
An induced elective abortion to terminate a pregnancy without medical reason 
 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (see Section 8.1.2.1) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 


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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 
Hospitalization for survey visits or annual physicals fall in the same category. 
 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias or convulsions that do not result in hospitalization 
 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
 
As an outcome event, progression to cirrhosis should not be included as AE. 
 
Death is an outcome of an AE, not an AE in itself. 


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 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 


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 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
 
Dose not changed – in case no action is taken regarding the study drug 


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 
Unknown 
 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
 
Recovered/resolved 
 
Recovering/resolving 
 
Not recovered/not resolved 
 
Recovered/resolved with sequelae 
 
Fatal 
 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
the last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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 
SAEs (including events related to study procedures) 
 
SADRs 
 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 


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 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key secondary endpoint 
The key secondary endpoint is: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other secondary endpoints 
The other secondary endpoints are: 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 


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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 


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 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS. 
 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
 
Full Intent-To-Treat Set (FITT): all randomized patients. 
 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS,and exploratory F1 cohorts (study population and efficacy data) will analyzed 
based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 


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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 


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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
Presence of type 2 diabetes (yes, no) 
 
Gender (male, female) 
 
Fibrosis (F2, F3) 
 
Geographic region (North America, Europe, South America, Rest of World) 
 
Race (Caucasian, Hispanic, Other) 
 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided =0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided =0.01 for resolution of NASH and two-sided =0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided =0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided =0.01 for resolution of NASH and 
two-sided =0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided =0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
 
=0.01 two-sided 
 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
 
Pooled variance 
 
Randomization ratio of 2:1 (elafibranor: placebo) 
 
8% response in the control group 
 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
 
72 month maximum follow-up 
 
=0.04 two-sided 
 
Annual event rate of 7% for the placebo group 
 
Hazard ratio of 0.75 in favor of the elafibranor group 
 
4% annual drop-out rate over 72 months 
 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 


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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e., 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 


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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 


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The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical Investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santiban˜ez C, Haim D, et al. Enhancement in liver nuclear factor-KB (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and 
fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. 
Epub 2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. 
Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al.,Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, 
and 
increases 
fatty 
acid 
oxidation 
in 
moderately 
obese 
men. 
Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell. Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell. Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 


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Appendices 


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APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1.1 France 
DATE: 
July 01, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
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Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
 
 
 
 
 
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Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
visits V1 to V7 
(Week 0 to Week 
72) 
V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 
5.1.1 and APPENDIX II: Adequate diet and lifestyle recommendations), 
alcohol restrictions (described in Section 5.1.2), and tobacco habits 
• 
Check concomitant/prior medication (described in Section 7.10 and 
APPENDIX III: Permitted/Non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 
6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 
onwards) (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record waist circumference (V1, V3, V5, and V7, only). 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
• 
Drug accountability (every visit from V2). 
• 
Ultrasonography of bladder and urinary tract (at V1 and V5 only) 
(described in Section 6.2.5). 
 
3.8.1 Long Term 
Treatment period 
visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment 
Period. The patient will be contacted at least 1 week before each visit to be 
reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 
5.1.1 and APPENDIX II: Adequate diet and lifestyle recommendations), 
alcohol restrictions (described in Section 5.1.2), and tobacco habits 
• 
Check concomitant/prior medication (described in Section 7.10 and 
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Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
APPENDIX III: Permitted/Non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 
6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 
and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4, with the 
exception of the final Vn visit) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF 
informed consent signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
• 
FibroScan (described in Section 6.2.4) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver 
cirrhosis, described in Section 6.1.1). Liver biopsy samples will be sent for 
central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; 
described in Table 2) and tested at a local laboratory prior to the liver 
biopsy. 
• 
Ultrasonography of bladder and urinary tract (at V8 then every year 
[V10, V12…]) (described in Section 6.2.5). 
 
3.11.3 Specific 
monitoring 
 
If the conditional approval for elafibranor is not obtained upon submission 
of interim analysis results, patients will be asked to come back for specific 
monitoring with visits every year over 4 years after the end of the long 
term treatment period. 
These specifics visits will include: dosage of AFP and osteocalcin, urine 
cytology, and ultrasonography of urinary tracts and bladder. 
4.1 Inclusion 
Criteria 
Addition of 1 inclusion criteria 
11. 
Patients following adequate life style recommendations. 
4.2 Exclusion 
criteria 
Addition of 2 exclusions criteria: 
19. Patients for whom life styles recommendations have never been 
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Clinical Trial GFT505-315-1  
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introduced. 
24. Patients with any history of cancer are excluded except patients with 
basal cell carcinoma. 
The numbering of exclusion criteria has been updated accordingly. 
5.1.3 Ultra-violet 
light exposure 
As a conservative approach patients will be advised to avoid extended 
ultra-violet light exposure without protection from V1 through to end of 
treatment visit (see Section 1.4.4.4). 
6.1.2.1 Laboratory 
assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and 
urinalysis) will be measured at every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and 
urine sample will be transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis (including urine 
microscopy) will be measured at all visits from V1 to EOT visits. 
6.1.2.4 Other 
parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory 
markers, as well as special glycemic and lipid parameters, will be measured at V1, 
V3, V5, and V7 during the First Treatment Period, at each visit during Long-term 
Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and 
V13 (at the time of the approximate 4 year biopsy). Alpha-fetoprotein (AFP) and 
osteocalcin will be tested every year from V1 up to end of study (at V1, V5, 
V8, V10, V12...). 
6.2.5 Bladder and 
urinary tract 
ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year 
from V1 up to end of study (at V1, V5, V8, V10, V12 …). 
 
 
Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 
• 
The version number and date were updated throughout the protocol 
 
 
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Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality,  progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 
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Clinical Trial GFT505-315-1  
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Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
• 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Exploratory objectives 
• 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
• 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
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Clinical Trial GFT505-315-1  
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o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
• 
To assess the tolerability and safety. 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine aminotransferase 
(ALT), obesity defined by a body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
• 
674 patients in placebo group  
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week-12 to Week -1 prior to randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Body Mass Index ≤45 kg/m². 
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4. Females participating in the study must either not be of childbearing potential (hysterectomy, 
bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation 
of menses for at least 12 months due to ovarian failure) or using efficient double contraception: 
hormonal contraception (including patch, contraceptive ring, etc), intra-uterine device, or other 
mechanical contraception method + condom or diaphragm or spermicide for the full duration of the 
study and for 1 month after the end of treatment. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic 
acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in anti-diabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e. implementation of a new anti-diabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfamides, or insulin. 
11. Patients following adequate life style recommendations. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol Consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
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Clinical Trial GFT505-315-1  
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o 
positive hepatitis C Virus RNA) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
19. Patients for whom life styles recommendations have never been introduced. 
 
Concomitant medications: 
20. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
21. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
22. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
23. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
24. Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
25. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic or psychiatric disease. 
26. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
27. Positive anti-human immunodeficiency virus antibody. 
28. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
29. Total bilirubin >25 µmol/L (1.5 mg/dL). 
30. International normalized ratio >1.4. 
31. platelet count <100,000/mm3. 
32. Serum creatinine levels >135 µmol/L (>1.53 mg/dL) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
33. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 
repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
34. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
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Clinical Trial GFT505-315-1  
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Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints  
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
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Clinical Trial GFT505-315-1  
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Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: February 2016 – March 2017 
• 
Recruitment period: February 2016 – December 2017 
• 
FPFV: February 2016 
• 
Interim analysis : August – October 2018 
• 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction and stroke events as 
defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 
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Clinical Trial GFT505-315-1  
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5. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to 
Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
10. ECG will be performed every 48 weeks starting at V9. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 
14. Ultrasonographic exam will be performed at V1 then approximately every year (at V5, V8, V10, V12…)  
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Clinical Trial GFT505-315-1  
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X = results available within 2 working days (routine analysis) * = batch analysis  
Abbreviations Ab = antibody; ACR = albumin–creatinine ratio; Ag = antigen; AFP= Alpha-fetoprotein; ALT = alanine aminotransferase; Apo = apolipoprotein; AST = aspartate 
aminotransferase; β-NAG = N-acetyl-β-D-glucosaminidase; BUN = blood urea nitrogen; Bx = biological assessment Visit x; CHI3L1 = chitinase-3-like protein 1; CK18 = cytokeratin 18; CPK = 
creatine phosphokinase; eGFR = estimated glomerular filtration rate; ELF = enhanced liver fibrosis; EOT = end of study treatment; FFA = free fatty acid; FGF = fibroblast growth factor; FIB-
4 = fibrosis 4 score; FLI = fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high 
density lipoprotein-C; HIV = human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 
18; INR = international normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-
associated lipocalin; NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing 
protein 3; PT  = prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = 
triglyceride; VLDL-C = very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:  
• 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
• 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
• 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
8. 
AFP and osteocalcin to be tested every year (V1,V5,V8,V10,V12,V14...). 
 
 
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Clinical Trial GFT505-315-1  
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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
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Clinical Trial GFT505-315-1  
 Protocol V1.1 France 1Jul2016 
Table of Contents 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 1.1 – FRANCE: 01 JULY 2016 ............................................................................................ 9 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 14 
TABLE OF CONTENTS ......................................................................................................................... 29 
TABLE OF TABLES .............................................................................................................................. 35 
TABLE OF FIGURES ............................................................................................................................ 35 
LIST OF ABBREVIATIONS .................................................................................................................... 36 
1. 
INTRODUCTION ........................................................................................................................ 39 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ............................................................................. 39 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ..................... 39 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .......... 41 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ........................................................................... 42 
1.4.1. 
Pharmacology ....................................................................................................... 42 
1.4.2. 
Safety pharmacology ............................................................................................ 43 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ................................. 43 
1.4.4. 
Toxicology ............................................................................................................ 44 
1.5. 
CLINICAL STUDIES ....................................................................................................... 45 
1.5.1. 
Phase I program ................................................................................................... 45 
1.5.2. 
Phase II program .................................................................................................. 46 
1.6. 
CONCLUSION ............................................................................................................... 49 
1.7. 
RATIONALE FOR STUDY POPULATION ........................................................................... 49 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ...................................................................... 50 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .......................................................................... 50 
1.9.1. 
Primary endpoint for application under conditional approval .................................... 50 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) ........................... 51 
1.10. 
RATIONALE FOR STUDY DURATION .............................................................................. 51 
1.11. 
RATIONALE FOR SAFETY MONITORING ......................................................................... 52 
2. 
TRIAL OBJECTIVES ................................................................................................................... 54 
2.1. 
PRIMARY OBJECTIVES .................................................................................................. 54 
2.1.1. 
Surrogate endpoint -Interim analysis...................................................................... 54 
2.1.2. 
Long-term endpoint .............................................................................................. 54 
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2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ....................................................... 54 
2.3. 
OTHER SECONDARY OBJECTIVES ................................................................................. 55 
2.4. 
EXPLORATORY OBJECTIVES.......................................................................................... 55 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .................................................................. 56 
2.6. 
SAFETY SECONDARY OBJECTIVES ................................................................................. 56 
3. 
TRIAL DESIGN .......................................................................................................................... 58 
3.1. 
NUMBER OF PATIENTS ................................................................................................. 58 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ............................................ 58 
3.3. 
DOSE ADJUSTMENT CRITERIA ...................................................................................... 59 
3.4. 
DURATION OF STUDY PARTICIPATION ......................................................................... 59 
3.5. 
STUDY PERIODS .......................................................................................................... 59 
3.6. 
SCREENING PERIOD ..................................................................................................... 59 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .......... 59 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ........................ 61 
3.6.3. 
Screening Phone Visit SPV (Week -1): .................................................................... 61 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ....................................................... 61 
3.7.1. 
Randomization Visit V1 (Week 0): .......................................................................... 62 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ................................... 62 
3.8. 
LONG-TERM TREATMENT PERIOD ................................................................................. 63 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ......................................................... 64 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ........................................... 64 
3.9. 
END OF STUDY TREATMENT VISIT................................................................................ 65 
3.10. 
FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ... 65 
3.11. 
OPTIONAL VISITS ........................................................................................................ 67 
3.11.1. 
Retesting screening visits ...................................................................................... 67 
3.11.2. 
Unscheduled visits ................................................................................................ 67 
3.11.3. 
Specific monitoring ............................................................................................... 67 
3.12. 
EXPLORATORY/ANCILLARY SUBSTUDY .......................................................................... 67 
4. 
PATIENT SELECTION ................................................................................................................. 68 
4.1. 
INCLUSION CRITERIA ................................................................................................... 68 
4.2. 
EXCLUSION CRITERIA .................................................................................................. 69 
5. 
TRIAL PROCEDURES ................................................................................................................. 72 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ................................ 72 
5.1.1. 
Standard diet and exercise recommendations ......................................................... 72 
5.1.2. 
Dietary and fluid restrictions .................................................................................. 72 
5.1.3. 
Ultra-violet light exposure ..................................................................................... 73 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ............. 73 
5.2.1. 
Handling of patient withdrawal .............................................................................. 73 
5.2.2. 
Permanent discontinuations of study drug .............................................................. 73 
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5.2.3. 
Patient discontinuation from the Study ................................................................... 74 
5.2.4. 
Patients lost to follow-Up....................................................................................... 75 
5.2.5. 
Replacement ........................................................................................................ 75 
5.2.6. 
Premature discontinuation of the study .................................................................. 75 
6. 
ASSESSMENTS .......................................................................................................................... 76 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .......................................................................... 76 
6.1.1. 
Histological assessments ....................................................................................... 76 
6.1.2. 
Biological assessments .......................................................................................... 77 
6.1.3. 
Constitution of biobank ......................................................................................... 78 
6.1.4. 
Pharmacokinetics evaluation .................................................................................. 78 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING ............................ 79 
6.2.1. 
Physical examination ............................................................................................. 79 
6.2.2. 
Vital signs............................................................................................................. 80 
6.2.3. 
Electrocardiogram ................................................................................................. 80 
6.2.4. 
FibroScan ............................................................................................................. 80 
6.2.5. 
Bladder and urinary tract ultrasonography .............................................................. 81 
6.2.6. 
Quality of life questionnaire ................................................................................... 81 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION 
RULES ......................................................................................................................... 81 
6.3.1. 
Creatine phosphokinase ........................................................................................ 81 
6.3.2. 
Liver function monitoring ....................................................................................... 82 
6.3.3. 
Threshold for diagnostic of cirrhosis ....................................................................... 83 
6.4. 
SAFETY DATA REVIEW ................................................................................................. 83 
6.5. 
CLINICAL EVENT COMMITTEE ....................................................................................... 83 
6.6. 
GUIDANCE FOR INVESTIGATORS .................................................................................. 84 
7. 
TREATMENTS............................................................................................................................ 88 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ....................................................................... 88 
7.2. 
PACKAGING AND LABELING .......................................................................................... 88 
7.2.1. 
Packaging............................................................................................................. 88 
7.2.2. 
Labeling ............................................................................................................... 88 
7.2.3. 
Dosage and administration of Elafibranor and placebo ............................................ 89 
7.2.4. 
Prior and concomitant medications......................................................................... 89 
7.3. 
STORAGE CONDITIONS ................................................................................................ 89 
7.4. 
DISPENSING OF TREATMENT ........................................................................................ 89 
7.5. 
TREATMENT REPLACEMENT .......................................................................................... 90 
7.6. 
PROCEDURE FOR BLINDING ......................................................................................... 90 
7.7. 
PROCEDURE FOR UNBLINDING ..................................................................................... 90 
7.8. 
STUDY DRUG COMPLIANCE .......................................................................................... 91 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ................................... 91 
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7.10. 
OTHER MEDICATION .................................................................................................... 91 
7.10.1. 
Handling of concomitant medication ...................................................................... 91 
7.10.2. 
Non-permitted medication ..................................................................................... 92 
7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) .......................................................................................................... 92 
7.10.4. 
Permitted medication ............................................................................................ 93 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT ......................................................................... 94 
8.1. 
DEFINITIONS ............................................................................................................... 94 
8.1.1. 
Adverse event ...................................................................................................... 94 
8.1.2. 
Serious adverse events ......................................................................................... 95 
8.1.3. 
Clarification on serious adverse events: .................................................................. 96 
8.1.4. 
Adverse drug reaction ........................................................................................... 97 
8.1.5. 
Unexpected adverse event .................................................................................... 97 
8.2. 
ASSESSMENTS ............................................................................................................. 97 
8.2.1. 
Intensity assessment ............................................................................................ 97 
8.2.2. 
Relation to the study treatment ............................................................................. 98 
8.2.3. 
Action taken and outcome ..................................................................................... 98 
8.3. 
REPORTING ................................................................................................................. 99 
8.3.1. 
Reporting an adverse event ................................................................................... 99 
8.3.2. 
Reporting a serious adverse event ......................................................................... 99 
8.3.3. 
Follow-up ........................................................................................................... 101 
8.4. 
POST STUDY REPORTING REQUIREMENTS .................................................................. 101 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS ....................................................... 101 
8.6. 
SPECIAL SITUATION REPORTS ................................................................................... 102 
8.6.1. 
Pregnancy .......................................................................................................... 102 
8.6.2. 
Medication error ................................................................................................. 102 
8.6.3. 
Misuse ............................................................................................................... 102 
8.6.4. 
Overdose ........................................................................................................... 103 
8.6.5. 
Abuse ................................................................................................................ 103 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ......................................................................... 104 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ....................................................... 104 
9.2. 
ENDPOINTS ............................................................................................................... 104 
9.2.1. 
Surrogate endpoint - resolution of NASH .............................................................. 104 
9.2.2. 
Long-term endpoint – time to clinical event/death ................................................ 104 
9.2.3. 
Key Secondary Endpoint ...................................................................................... 105 
9.2.4. 
Other Secondary Endpoints ................................................................................. 105 
9.2.5. 
Exploratory endpoints ......................................................................................... 106 
9.3. 
ANALYSIS SETS .......................................................................................................... 106 
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9.4. 
ANALYSIS OF PRIMARY ENDPOINTS............................................................................ 107 
9.4.1. 
Resolution of NASH ............................................................................................. 107 
9.4.2. 
Long-term endpoints ........................................................................................... 107 
9.5. 
OTHER STATISTICAL ANALYSIS .................................................................................. 108 
9.5.1. 
Key secondary endpoint ...................................................................................... 108 
9.5.2. 
Other secondary endpoints .................................................................................. 108 
9.5.3. 
Subgroup analyses .............................................................................................. 109 
9.5.4. 
Exploratory analyses ........................................................................................... 109 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ................................................................... 109 
9.7. 
SAMPLE SIZE CALCULATION ....................................................................................... 110 
9.7.1. 
Resolution of NASH ............................................................................................. 110 
9.7.2. 
Time to clinical event/death ................................................................................. 110 
9.8. 
SAFETY ANALYSIS ...................................................................................................... 111 
9.8.1. 
Interim analysis .................................................................................................. 111 
9.9. 
BLINDED REASSESSMENT ........................................................................................... 112 
10. 
DATA HANDLING AND RECORD KEEPING ................................................................................. 113 
10.1. 
CRF AND SOURCE DOCUMENTS .................................................................................. 113 
10.2. 
RETENTION OF RECORDS ........................................................................................... 113 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................ 115 
11.1. 
QUALITY CONTROL & MONITORING PROCEDURES ...................................................... 115 
11.2. 
ETHICAL PRINCIPLES ................................................................................................. 116 
11.3. 
QUALITY ASSURANCE ................................................................................................. 116 
12. 
ETHICS AND REGULATORY ...................................................................................................... 117 
12.1. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ......................... 117 
12.2. 
COMPETENT AUTHORITY ........................................................................................... 118 
12.3. 
PATIENT INFORMATION AND CONSENT ...................................................................... 118 
12.4. 
PATIENT CONFIDENTIALITY ....................................................................................... 118 
12.5. 
DEFINITION OF THE END OF THE RESEARCH .............................................................. 119 
13. 
FINANCING AND INSURANCE .................................................................................................. 120 
13.1. 
FINANCIAL ISSUES ..................................................................................................... 120 
13.2. 
INSURANCE AND PATIENT INJURY .............................................................................. 120 
14. 
STUDY RESULTS AND PUBLICATION POLICY ............................................................................ 121 
14.1. 
STUDY REPORT .......................................................................................................... 121 
14.2. 
CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION ............................................................................................................ 121 
15. 
REFERENCES LIST ................................................................................................................... 123 
APPENDICES .................................................................................................................................... 126 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 127 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 136 
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APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 137 
APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 139 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 140 
 
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 Table of Tables 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 21 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 25 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 81 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 86 
 
Table of Figures 
Figure 1: STUDY DURATION AND VISIT SCHEDULE ........................................................................... 28 
 
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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
AFP 
Alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
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GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
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SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV-Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 
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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 
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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 
Lipid peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPARγ reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPARγ -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
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1.4.4.4. 
Photoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV-Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of photoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 
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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 
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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 
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(-20% to -35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. . Serious adverse events (SAE) were reported 
in 27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor  120 mg/d). Of 
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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor  120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 
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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 
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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatine 
ration, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 
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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
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2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
• 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 
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• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
• 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
• 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver function parameters 
• 
renal function parameters (including urinalysis) 
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• 
cardiac function parameters 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 
 
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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 
• 
Physical examination (described in Section 6.2.1). 
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•
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits.
•
Record vital signs (described in Section 6.2.2).
•
Record height, weight, and waist circumference.
•
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10
and APPENDIX III: Permitted/Non-permitted medication)
•
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1.
•
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and
Section 8).
The Screening biological assessment (SB1 will be scheduled at SV1. 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
•
Blood samples (described in Table 2).
•
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed).
•
Urinalysis dipstick.
•
Urinary pregnancy test (for women of childbearing potential only [WOCBP]).
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 33, 
and 34 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 

First 3 digits corresponding to the ISO numeric country code (this number will be predefined),

Next 2 digits corresponding to the site number (this number will be predefined),

Last 2 digits corresponding to the numerical order of the patient entry at the study site.
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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 
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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
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• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record waist circumference (V1, V3, V5, and V7, only). 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
• 
Drug accountability (every visit from V2) 
• 
Ultrasonography of bladder and urinary tract (at V1 and V5 only) (described in Section 6.2.5). 
Additional procedures to be performed at V7 are: 
• 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
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3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
• 
FibroScan (described in Section 6.2.4) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy 
• 
Ultrasonography of bladder and urinary tract (at V8 then every year [V10, V12…]) (described in 
Section 6.2.5). 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety, and IP compliance control. If any information during this phone contact requires a visit, 
the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS 
registration will be performed for each phone visit. 
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3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, and Figure 1. 
The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.3) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
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Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
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3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization.  
• 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc).Unscheduled visits will be needed for 
patients who may require further follow-up due to safety. 
3.11.3. 
Specific monitoring 
If the conditional approval for elafibranor is not obtained upon submission of interim analysis results, 
patients will be asked to come back for a specific monitoring visit every year over 4 years after the end of 
the long term treatment period. 
These specifics visits will include: dosage of alpha-fetoprotein (AFP) and osteocalcin, urine 
cytology, and ultrasonography of urinary tracts and bladder. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 
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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral 
oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses 
for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal 
contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical 
contraception method + condom or diaphragm or spermicide for the full duration of the study and for 
1 month after the end of treatment. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 
treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or 
ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy.  
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions:  
• 
No change in dose for patients treated by GLP-1 agonists 
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• 
No qualitative change (i.e. implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfamides, or insulin. 
11. Patients following adequate life style recommendations. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients. 
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
• 
Positive hepatitis B surface antigen (HBsAg) 
• 
HCV RNA 
• 
Suspicion of drug-induced liver disease 
• 
Alcoholic liver disease 
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• 
Autoimmune hepatitis 
• 
Wilson’s disease hemochromatosis 
• 
Primary biliary cirrhosis, primary sclerosing cholangitis 
• 
Genetic hemochromatosis 
• 
Known or suspected HCC 
• 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
19. Patients for whom life styles recommendations have never been introduced. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
20. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
21. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
22. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 
23. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
24. Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
25. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
26. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
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In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
27. Positive anti-human immunodeficiency virus (HIV) antibody. 
28. AST and/or ALT >10 x the upper limit normal (ULN). 
29. Total bilirubin >25 µmol/L (1.5 mg/dL). 
30. INR >1.4. 
31. Platelet count <100,000/mm3. 
32. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
33. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
34. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 
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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, and 
Figure 1) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
• 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
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• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.1.3. 
Ultra-violet light exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to end of treatment visit (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
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• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
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Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 
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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gage needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 
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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory 
(GENFIT- Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 
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The V1 to Vn total chemistry panel and urine analysis (including urine microscopy) will be measured at all 
visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). Alfa-fetoprotein and osteocalcin will be tested 
every year from V1 up to end of study (at V1, V5, V8, V10, V12...). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
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Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 
Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
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6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.2.1. 
Important points for clinical blood pressure measurement: 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 
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Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e. ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Bladder and urinary tract ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year from V1 up to end of study (at 
V1, V5, V8, V10, V12…). 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 
must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
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6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Decrease in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
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6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
• 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
• 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 
• 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visitin the Long-
term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or a any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or 
ascites, then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will 
have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction and stroke events 
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as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, 
and unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
The safety and tolerability of GFT505 were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication.  
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
• 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
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All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 
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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI.  
Based on the findings of non-clinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, GFT505 may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014).  
As such, all clinical trials with GFT505 including women of childbearing potential request a negative 
pregnancy test before randomization, with effective contraceptive measures throughout the sudy. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between GFT505 and contraceptive steroids, the exclusive use of hormonal contraceptive methods during 
clinical trials should be avoided, and they should be accompanied by barrier methods.    
Conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with GFT505. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in phase 2 trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
GFT505 treatment, up to 1 month after end of study treatment. 
 
 
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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed) , and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 
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value defined in the supply strategy. Following randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
• 
Blister identification 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 
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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
• 
Glitazones (pioglitazone & rosiglitazone) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
• 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
• 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 
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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfamides 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfamides and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 
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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 
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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g. wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
As an outcome event, progression to cirrhosis should not be included as AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
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• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
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• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
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• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening visit and ends at the 
last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 
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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 
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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 
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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 
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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 
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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
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• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
• 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 
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• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. . Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
• 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS,and exploratory F1 cohorts (study population and efficacy data) will analyzed 
based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 
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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 
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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Hispanic, Other) 
• 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided α=0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided α=0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided α=0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and 
two-sided α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. . 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e. 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 
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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
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The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 
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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 
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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 
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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 
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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 
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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 
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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 
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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 
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3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
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5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santiban˜ez C, Haim D, et al. Enhancement in liver nuclear factor-kb (nf-kb) and 
activator protein 1 (ap-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-
acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. Epub 
2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al.,Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 
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stress, 
and 
increases 
fatty 
acid 
oxidation 
in 
moderately 
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Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
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delta regultate macrophage polarization and insulin sensitivity. Cell. Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell. Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
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Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 
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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
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About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 
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Appendices 
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APPENDIX I – World Medical Association Declaration of Helsinki 
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APPENDIX IV: Alcohol comparison table 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 
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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 
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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
2.1 France 
DATE: 
January 12, 2017 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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AMENDMENT 1: 12 JANUARY 2017 
Amendment 2.1 - France addresses inconsistencies in the original protocol and increases clarity. It also details the statistical analyses to be consistent with the Statistical 
Analysis Plan. Revisions were made to protocol sections noted below as well as to the study synopsis, the study general assessment schedule (Table 1), study biological 
assessment schedule (Table 2), study duration and visit schedule (Figure 1), and throughout the protocol text as required. Added text is bolded; deleted text is struck 
through. 
Summary of major changes to the protocol: 
Section 
New Text 
Table 2: 
STUDY BIOLOGICAL 
ASSESSMENT SCHEDULE 
(amendments not 
described anywhere else in 
protocol) 
Screening Visit 1 - chemistry panel 
HbA1c32, fasting plasma glucose, Insulin (fasting), HOMA –IR, creatinine, eGFR3, GGT, AST, ALT, CPK32, alkaline phosphatase, total and conjugated bilirubin, sodium, and 
TG, and MELD score 
V1 to Vn total chemistry panel 
HbA1c, fasting plasma glucose, creatinine, eGFR, GGT, AST, ALT, CPK, alkaline phosphatase, total proteins, albumin, electrolytes (sodium, potassium, chloride, calcium), uric 
acid, urea (BUN), total and conjugated bilirubin, hsCRP, total cholesterol, nonHDL-C, HDL-C, TG, calculated VLDL-C, ApoAI, ApoB, and calculated LDL-C, and MELD score 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma  while plasma and serum samples are to be taken 
should be retrieved at every visit ONLY for patients who have signed the pharmacogenomics genetic and biomarker ICF. 


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Section 
New Text 
Figure 2:  
PREGNANCY TESTING 
SCHEDULE FOR WOMEN 
OF CHILDBEARING 
POTENTIAL 
New figure included for pregnancy testing schedule for women of childbearing potential. Appropriate text added throughout protocol as 
required. 
 
Section 1.9.2  
Primary endpoint for 
clinical outcome 
(postapproval 
confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of elafibranor on the progression 
to cirrhosis, all-cause mortality, and liver-related clinical outcomes as measured by the onset time to first occurrence of any of the listed 
adjudicated events (clinical outcomes composite endpoint). 


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Section 
New Text 
Section 1.11 
Rationale for safety 
monitoring 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the renal safety markers (plasmatic 
or urinary parameters), including but not limited to albumin-creatinine ration, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), 
N acetyl β D -glucosaminidase β-NAG, kidney injury molecule-1 (KIM 1). Serum creatinine, and modification of diet in renal disease 
(MDRD) derived estimated glomerular filtration rate (eGFR) creatinine clearance, and the results of urinalysis (dipstick) will be 
reported at each visit, as well as blood urea nitrogen. 
Section 2.1.2 
Long-term endpoint 
Note: this change was also 
implemented in Section 
3.10 and Section 9.2.2 
 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence The onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites  
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to hospitalization or 
transfusion). 
Section 3.6.1 
Screening visits SV1 
(Week -12 to Week -8) and 
SV2 (Week -12 to 
Week -4): 
 
• Signature of informed consent witnessed by the Investigator or designated person. Note: The signature of the informed consent 
may also be performed before SV1.  
• Check concomitant/prior medication (within 30 days 6 months prior to Screening) (described in Section 7.12 and APENDIX III: 
Permitted/non-permitted medication) 
• Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for central confirmation of NASH diagnosis 
(described in Section 6.1.1.2). This historical diagnostic biopsy should be obtained within 6 months prior to the planned Randomization 


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Section 
New Text 
Screening Visit (V1). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, total bilirubin, INR), at least 2 
consecutive assessments in at least 8 weeks apart between visit SV1 and V1 should be performed. Visits SV1 and V1 should be scheduled 
at least 8 weeks apart in order to have 2 consecutive baseline values of AST, ALT, total bilirubin, and INR for DILI 
adjudication (using SV1 and V1 kits).according to this requirement. 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without waiting for HCV Ab 
results. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR), or creatine phosphokinase (CPK) results or additional 
testing of hepatitis C virus (HCV) RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 13,12, 30, and 31 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they agree to participate in the study 
and sign the ICF. Each patient who will have has signed the ICF will be allocated a patient number composed of 79 digits which is 
generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 23 digits corresponding to the site number (this number will be predefined), 
 Last 23 digits corresponding to the numerical order of the patient entry at the study site. 
Section 3.7.2   
First Treatment Period 
visits V1 to V7 (Week 0 to 
Week 72) 
The following procedures will be performed at each of the 12 week visits from V1 to V7 : 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous visit (for WOCBP 
only, every visit from V1 


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Section 
New Text 
Section  3.8.1 
Long-term Treatment 
Period Visits (V8 to Vn) 
The following procedures will be performed at each visit from V8 to Vn: 
• 
Quality of life assessment (V8, V9, V11, and every 48 weekly weeks thereafter Section 6.2.6) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous visit (for WOCBP 
only, every visit from V1 
Section 3.8.2  
Long-term Treatment 
Period phone visits (PV1 to 
PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and lifestyle, concomitant 
medications, clinical outcomes, safety, home pregnancy test results, and IP compliance control. If any information during this phone 
contact requires a visit, the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be 
performed for each phone visit. 
Section 3.9  
End of Study Treatment 
Visit 
 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return (if required). The 
following procedures will be performed at the EOT Visit: 
• IXRS registration 
• Physical examination (described in Section 6.2.1) 
• Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits 
• Check concomitant/prior medication (described in Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• Quality of life assessment (described in Section 6.2.6) 
• Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• Blood samples (described in Table 2) 


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Section 
New Text 
• Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent signed) 
• Urinalysis and urinary dipstick (described in Table 2) 
• Urinary pregnancy test (for WOCBP only) 
• Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2) since previous visit (for WOCBP 
only) 
• Record waist circumference 
• 12-lead ECG (described in Section 6.2.4) 
• Drug accountability. 
3.11.1 
Retesting screening visits 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test 
and maximum 2 weeks prior to planned Randomization.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
Section 4.1 
Inclusion criteria 
3. 
BMI ≤45 kg/m2 
3. Females participating in this the study must either not be of nonchildbearing potential (hysterectomy, bilateral oophorectomy, 
medically documented ovarian failure, or >50 years of age with or using highly efficient contraception for the full duration of 
the study and for 1 month after the end of treatment, as described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure) or using efficient double contraception; hormonal,   


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Section 
New Text 
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient) 
o Using a highly effective nonhormonal method of contraception (including patch, contraceptive ring, etc bilateral tubal 
occlusion, vasectomized partner or intra-uterine device, or opther mechanical) 
o 
Double contraception method + condom or diaphragm with barrier AND highly effective hormonal method of 
contraception (oral, intravaginal or spermicide for the full duration of the study and for 1 month after the end of treatment 
transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; 
oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at least 1 month prior to 
Randomization. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, change 
in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., implementation of a new 
anti-diabetic therapy) for patients treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter 
(SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are 
allowed in the 6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ judgment, except 
for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the end of treatment. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by anti diabetic drugs, no change is allowed 


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Section 
New Text 
within 6 months prior to diagnostic liver biopsy, under the following conditions:  
• no change in dose for patients treated by GLP 1 agonists  
• no qualitative change up to Randomization (i.e., implementation of a new anti diabetic therapy) for patients treated with metformin, 
gliptins, sulfamides, or insulin. 
 .• no qualitative change up to 72 week of treatment (V7) (i.e., implementation of new drug) for patients treated with sodium/glucose 
cotransporter 2 (SGLT2) inhibitors. 
Section 4.2 
Exclusion criteria 
1. 
Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the course of the study. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening such as: acute cardiovascular 
episode, stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization 
procedures). 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to donate blood or blood products at 
any time during the trial and in the 2 months following the end of the study. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV C infection, or positive HCV Ab at Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 


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Section 
New Text 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the recommendations of National 
Law in force applicable to clinical Trials. 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, or ezetimibe, or nonfibrate lipid 
lowering drugs before Screening may participate if the dosage has been kept constant for at least 2 months prior to Screening. 
28. Total Conjugated bilirubin >25 µmol/L (1.50 mg/dL) due to altered hepatic function. NOTE: Gilbert Disease patients are 
allowed into the study. 
29. INR >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
Section 5.1.3  
Home pregnancy test 
for women of 
childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy test kits will be 
supplied at each visit to WOCBP and these are to be performed as per the kit instructions every 4 weeks between study 
visits. Negative results are to be reported at the next scheduled visit or telephone visit (see Table 1 and Figure 2). In the 
event of a positive result the patient must discontinue study drug immediately and report the result to the Investigator as 
soon as possible (see Section 8.6.1). 
5.3. 
Patient rescreening 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which allows him/her 
to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening the patient will need to sign a 
new informed consent, will be entered as a new patient, with a new patient number. 


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Section 
New Text 
6.1.2.2 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during the study on WOCBP. These 
tests will also be given to the WOCBP to perform a pregnancy test at home every 4 weeks in between visits (see Section 
5.1.3).  
6.1.4 Pharmacokinetic 
evaluation 
Section removed and all text throughout relating to pharmacokinetic assessments/analysis removed. This will be addressed through a 
specific sub-study protocol. 
Section 9  
Statistical methods and 
data analysis 
In all circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first approved version of the SAP 
should be available within 3 months of protocol submission first patient randomized and before the first DSMB meeting. 
9.4.1 
Resolution of NASH 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of the 72 week treatment period 
will be summarized by treatment group. The main analysis will be performed using a logistic regression model, with fixed terms for 
treatment, type 2 diabetes (yes, no), gender (male, female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to 
calculate the odds ratio (elafibranor/placebo) and 99% 95% confidence interval. The main confirmatory analysis will be performed when 
approximately 50% of patients (at least 1023) F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
9.4.2 
Long-term endpoints 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage, 
and baseline NAS. The Cox proportional hazards model will be used to calculate the hazard ratio (elafibranor/placebo) and 96% 95% 
confidence interval. This will be performed when at least 456 patients experience a clinical event/death. The time to clinical 
event/death and time to first cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s 
model, log rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36  


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Section 
New Text 
Section 9.5.3  
Subgroup analyses 
• Race (Caucasian, hispanic, Other) 
• Ethnicity (Hispanic, not Hispanic) 
• Age (<5560, ≥5560 years). 
Section 9.6.  
Strategies to control type I 
error 
The overall type I error for this study is two sided α=0.05. The alpha for the primary endpoints will be split 20%/80%, with two sided 
α=0.01 for resolution of NASH and two sided α=0.04 for time to clinical event/death. The overall type I error for the primary endpoints in 
this study is two-sided α=0.05. The alpha for the primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH 
and two-sided α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. If the resolution of NASH without 
worsening of fibrosis endpoint is statistically significant, the key secondary endpoint, improvement of fibrosis according to NASH CRN 
scoring, will be tested in a confirmatory manner with a two-sided α=0.501. 
Section 9.9.  
Blinded reassessment 
Interim analysis 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or discontinued from the 72 week 
treatment period. The number of patients enrolled may be increased at this time and/or total duration extended. No adjustment will be 
made to the targeted number of events required for the final analysis of the long term endpoint, so no adjustment for control of type I 
error should be required for this reassessment. An adaptive design interim analysis will be performed after 140 primary events 
(approx. 30% of the 456 required events) have been accrued. The interim analysis will be performed by an unblinded team 
separate from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and provide 
final recommendations regarding trial termination due to futility and adjustment of the target number of primary events. 
Details will be in the DSMB Charter and SAP. 




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Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 
• 
the version number and date were updated throughout the protocol 
• 
typographical errors and formatting were corrected throughout the protocol 
• 
abbreviation was added to the list of abbreviations for FITT 
• 
amendment of study duration dates 
• 
amendment of study contact details: amendment of study drug supplier contact information: 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
Monitor 
 
 
 
 
 
 
 
 
 
Project 
Director 
 
  
 
 
 
 
Senior Project 
Manager 
 
 
 
IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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• 
Section 4.2. Exclusion Criteria 
Minor changes to exclusion criteria 1, 5, 6, 12, 21, 27, and 32 to clarify requirements 
• 
Section 5.1.1 Standard Diet and exercise recommendations 
Text deleted to remove specific wording for compliance question 
• 
Section 5.1.4 Sun exposure 
Title & text amended for increased clarity. 
• 
Section 6.1.1.1. Recommendations related to liver biopsy 
Note: Liver biopsy should be performed according to the good practices and local hospital 
standards, including the required exams prior to or on the day of the biopsy; Thus, the 
recommendations were simplified as below, to allow sites to follow their local requirements. 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the 
biopsy, and the risks to the patient should not outweigh the potential benefits. This will be 
assessed by the Investigator according to local practice. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of 
imaging of the liver within the preceding weeks. This will allow the detection of abnormal anatomy 
in the area of the proposed biopsy. 
 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding 
adequate reading, other available slides or new slides to be prepared from an available 
block of tissue may be requested to the site. 
• 
Section 6.1.2. Biological assessments 
Text amended for increased clarity of procedural requirements 
• 
Section 6.1.2.3 Serology (SB1) 
Text amended for increased clarity of procedural requirements 
• 
Section 6.2.1. Physical examination 
Text amended for increased clarity of procedural requirements. 
• 
Section 6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest 
and the lowest rib in cm during expiration. The measuring tape should be snug but not 
compressing the skin and held parallel to the floor. The measurement is to be made at 
normal respiration. 
• 
Section 6.2.5 FibroScan 
Text updated for increased clarity of procedural requirements 
• 
Section 6.2.6 Bladder and urinary tract ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year from V1 up to end of study 
(at V1, V5, V8, V10, V12…). Where possible ultrasonographic exam must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.   
 


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• 
Section 6.3.1 Creatine phosphokinase 
Text amended for increased clarity of procedural requirements  
• 
Section 6.3.2 Liver function monitoring 
In all cases, whether baseline AT values are normal or elevated, an increase of 
AT>10 x ULN will lead to permanent discontinuation of the patient from study drug, 
and scheduling of EOT visit (Section 3.9). 
• 
Section 6.3.2.1 Monitoring of patients with normal baseline aminotransferase values 
Text amended for increased clarity of monitoring requirements 
• 
Section 6.3.2.2 Monitoring of patients with increased baseline aminotransferase AT values 
Text amended for increased clarity of monitoring requirements 
• 
Section 6.3.2.3 Monitoring of all patients 
Section deleted, text amended and moved to Section 6.3.2.1 
• 
Section 6.3.3. Threshold for diagnosisic diagnosis of cirrhosis 
Text amended for increased clarity of procedural requirements 
• 
Section 6.4. Safety & efficacy data review 
An independent DSMB will be established in order to review the progress of the study and to 
perform a safety data review on a regular basis during the trial to protect patient welfare and 
preserve study integrity. The DSMB will also review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and 
adjustment of the target number of primary events. A detailed description of the 
interim analysis procedures and decision-making process will be provided in the DSMB 
Charter. 
The DSMB will consist of at least 54 experienced physicians (1 each of endocrinologist, 
1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom 
will be independent of the participants in the study. TheA DSMB Charter will define the role, 
responsibilities, rules, and tasks of the DSMB. 
• 
Section 6.5. Clinical event committee 
The CEC will specifically assess and adjudicate conduct adjudication of all disease progression 
events included in the primary composite efficacy long-term endpoint (Section 1.9.2, except for 
histological cirrhosis), all DILI events, and all major cardiovascular events: i.e., cardiovascular 
death, nonfatal myocardial infarction and stroke events as defined in the CEC chartermanual. 
The CEC will be comprised of 2 hepatologists, and 1 2 cardiologists and 1 endocrinologist, all 
of whom will be independent of the participants in the study. 
• 
Section 6.6.1 summary of safety data 
Text updated for consistency with current Investigator’s Brochure (Version 21). 
• 
Section 6.6.3 Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the 
therapeutic potential of elafibranor in metabolic diseases including NASH. Moreover, 


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the Phase IIb trial demonstrated the efficacy of elafibranor at the therapeutic dose of 
120 mg on a clinically meaningful primary endpoint, resolution of histological NASH 
without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that 
elafibranor, at 120 mg daily, improved fibrosis indirectly through the resolution of 
NASH. Importantly, elafibranor 120 mg concomitantly improved the cardiometabolic 
risk 
profile 
of 
the 
patients 
by 
decreasing 
plasma 
triglycerides, 
total 
and 
LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin 
resistance, and glucose homeostasis. Together these results position elafibranor as a 
drug candidate to treat NASH with the objective to block fibrosis evolution and 
ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns 
associated with elafibranor treatment, thus providing a favorable efficacy/safety 
profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring 
Board (DSMB) is to be established in order to review the safety of the treatment during 
the trial in an unblinded manner, to protect patient welfare and preserve study 
integrity. The safety assessments will be performed on a regular basis, every 6 months 
after Randomization of the first patient. The DSMB will consist of 5 experienced 
physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, and 
1 nephrologist) and 1 statistician, all independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring 
including assessment of many safety parameters and follow-up of the disease 
progression, mainly through noninvasive measures including FibroScan. 
• 
Section 7.2.2. Labeling 
Text amended to reflect updated regulations 
• 
Section 7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION 
Text amended for increased clarity  
Section 7.12.1. Handling of concomitant medication 
Text amended for increased clarity  
• 
Section 7.12.2. Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) 
Text amended for increased clarity and to reflect updates in inclusion/exclusion criteria and 
Appendix III 
• 
Section 7.12.3. Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) 
Text amended for increased clarity and to reflect updates in inclusion/exclusion criteria and 
Appendix III 


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• 
Section 8.1.2. Serious adverse events 
• 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the 
Investigator) to any study-specific procedure (e.g. wash out period, laboratory testing procedure, 
liver biopsy) must be reported as an SAE.  
• 
Section 8.1.2.2 Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays 
overnight in the hospital. An overnight stay is defined by hospitalization of 24 hours. 
Visits to the emergency room will not be considered hospital admission. 
• 
Section 8.1.3. Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation As 
an outcome event, progression to cirrhosis should not be included as an AE. 
• 
Section 8.3.1. Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient the last study visit. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and 
ends at study end for each patient the last study visit. 
• 
Section 8.3.2. Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit 
study end for each patient. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 
Events that are identified as potential primary efficacy endpoints for long-term evaluation will 
NOT be reported as SAEs unless it is determined by the adjudication committee that the event 
does not meet the predefined criteria for an endpoint. Events that are identified as potential 
primary efficacy endpoints for long-term evaluation that are not confirmed by adjudication will be 
reported as described with the start of the reporting time window being the time of negative 
adjudication decision. 
• 
Section 8.6.1. Pregnancy  
Text amended to add requirement for pregnant female partners to sign informed consent for 
pregnancy reporting 
• 
Section 9 Statistical methods and data analysis 
The first approved version of the SAP should be available within 3 months of protocol submission 
first patient randomized and before the first DSMB meeting. 
• 
Section 9.2.2 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on The long term endpoint of 
clinical outcomes described as is a composite endpoint composed of death due to any cause, liver 
cirrhosis, and the full list of portal hypertension/cirrhosis related events 


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• 
Section 9.5.1. Key secondary endpoint 
The analysis will be performed at the time of the interim analysis surrogate endpoint analysis 
when approximately 50% of patients (at least 1023) of patients with fibrosis stage F2 and F3 
have completed the 72 week treatment period or discontinued from the study. The null 
hypothesis will be tested at the two-sided 0.01 alpha level. 
• 
Section 9.5.2. Other secondary endpoints 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed 
terms for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured 
covariance matrix will be used for this analysis. The statistical model will be used to calculate the 
mean treatment difference and 95% confidence interval. If the data does not meet the required 
assumptions for parametric tests, the data will be analyzed using a nonparametric analysis of 
covariance method of Koch et al.37 Wilcoxon rank sum test. The median treatment difference 
and 95% confidence interval will be calculated using the Hodghes Lehmann method. 
• 
Section 9.8 Safety Analysis 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment 
group using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint 
and change from baseline will also be summarized using descriptive statistics. 
• 
Section 10.1. CRF Case report form and source documents  
Text amended for increased clarity 
• 
Appendix V 
Text amended to remove site number from wallet 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
Hepatocellular carcinoma 
• 
the onset of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis (SAF) 
activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory objectives 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and NAFLD 
Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 


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o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the tolerability and safety. 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver markers 
o 
renal biomarkers (including urinalysis) 
o 
cardiac biomarkers 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by a 
body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or 
homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement 
for presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is 
confirmed as well as any other event listed in the long-term composite endpoint, patients will be 
discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
• 
674 patients in placebo group  
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~250 centers 
Number of participating countries: ~25 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, 
Mexico, Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week-12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  


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o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented 
ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the patient)  
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
-Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at 
least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, 
and lobular inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of 
normal value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  
o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before Screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation). 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months 
prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver 
biopsy until the end of treatment. 
 
10. Patients following adequate life style recommendations 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c 
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal 
HbA1c (HbA1c >9.0%) leads to exclusion. 


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6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or 
positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease  
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
18. Patients for whom life styles recommendations have never been introduced. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, 
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage 
has been kept constant for at least 2 months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
24. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
25. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
26. Positive anti-human immunodeficiency virus antibody. 
27. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN). 


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28. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients 
are allowed into the study. 
29. International normalized ratio >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). 
33. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints  
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 


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o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – March 2017 
• 
Recruitment period: March 2016 – March 2018 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q4 2018 – Q1 2019 
• 
LPLV (LTTP): March 2022 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist all of whom will be 
independent of the participants in the study. 
 








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6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. In the LTTP the first ECG will be performed at V9 and then every 48 weeks. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively), 
and every 48 weeks thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 
14. Ultrasonographic exam will be performed at V1 then approximately every year (at V5, V8, V10, V12…). Where possible ultrasonographic exam must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.   
 








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4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic and 
biomarker ICF. 
6. 
Visits SV1 and V1 should be scheduled at least 8 weeks apart in order to have 2 consecutive baseline values of AST, ALT, total bilirubin, and INR for DILI adjudication. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
8. 
AFP and osteocalcin to be tested every year (V1, V5, V8, V10, V12, V14...). 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
AMENDMENT 1: 12 JANUARY 2017 ...................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 28 
TABLE OF CONTENTS ....................................................................................................................... 45 
TABLE OF TABLES ............................................................................................................................ 51 
TABLE OF FIGURES .......................................................................................................................... 51 
LIST OF ABBREVIATIONS .................................................................................................................. 52 
1. 
INTRODUCTION ................................................................................................................. 55 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 55 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 55 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 57 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 58 
1.4.1. 
Pharmacology .......................................................................................................... 58 
1.4.2. 
Safety pharmacology ................................................................................................ 58 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 58 
1.4.4. 
Toxicology ............................................................................................................... 60 
1.5. 
CLINICAL STUDIES ............................................................................................................. 61 
1.5.1. 
Phase I program ...................................................................................................... 61 
1.5.2. 
Phase II program ..................................................................................................... 62 
1.6. 
CONCLUSION ..................................................................................................................... 64 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 65 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 66 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 66 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 66 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) ............................... 66 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 67 
1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 67 
2. 
TRIAL OBJECTIVES ............................................................................................................. 69 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 69 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 69 


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2.1.2. 
Long-term endpoint ................................................................................................. 69 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS ................................... 69 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 70 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 70 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP ......................................................................... 71 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 71 
3. 
TRIAL DESIGN .................................................................................................................... 72 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 72 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 72 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 73 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 73 
3.5. 
STUDY PERIODS ................................................................................................................. 73 
3.6. 
SCREENING PERIOD ........................................................................................................... 73 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): ............... 73 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 75 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 75 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 75 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 76 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 76 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 77 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 78 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 78 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 79 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 80 
3.11. OPTIONAL VISITS .............................................................................................................. 81 
3.11.1. 
Retesting screening visits .......................................................................................... 81 
3.11.2. 
Unscheduled visits ................................................................................................... 81 
3.11.3. 
Specific monitoring ................................................................................................... 81 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY ................................................................................. 82 
4. 
PATIENT SELECTION .......................................................................................................... 83 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 83 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 84 
5. 
TRIAL PROCEDURES ........................................................................................................... 87 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 87 
5.1.1. 
Standard diet and exercise recommendations ............................................................. 87 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 87 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 88 
5.1.4. 
Sun exposure .......................................................................................................... 88 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 88 


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5.2.1. 
Handling of patient withdrawal .................................................................................. 88 
5.2.2. 
Permanent discontinuations of study drug .................................................................. 88 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 89 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 90 
5.2.5. 
Replacement ........................................................................................................... 90 
5.2.6. 
Premature discontinuation of the study ...................................................................... 90 
5.3. 
PATIENT RESCREENING ...................................................................................................... 91 
6. 
ASSESSMENTS ................................................................................................................... 92 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 92 
6.1.1. 
Histological assessments ........................................................................................... 92 
6.1.2. 
Biological assessments ............................................................................................. 93 
6.1.3. 
Constitution of biobank ............................................................................................. 94 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 95 
6.2.1. 
Physical examination ................................................................................................ 95 
6.2.2. 
Waist circumference ................................................................................................. 95 
6.2.3. 
Vital signs ............................................................................................................... 95 
6.2.4. 
Electrocardiogram .................................................................................................... 96 
6.2.5. 
FibroScan ................................................................................................................ 96 
6.2.6. 
Bladder and urinary tract ultrasonography .................................................................. 96 
6.2.7. 
Quality of life questionnaire ...................................................................................... 96 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 97 
6.3.1. 
Creatine phosphokinase ............................................................................................ 97 
6.3.2. 
Liver function monitoring .......................................................................................... 97 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 98 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 99 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 99 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 99 
6.6.1. 
Summary of safety data............................................................................................ 99 
6.6.2. 
Safety data conclusion ............................................................................................ 102 
6.6.3. 
Benefit/risk assessment .......................................................................................... 102 
7. 
TREATMENTS ................................................................................................................... 103 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................ 103 
7.2. 
PACKAGING AND LABELING .............................................................................................. 103 
7.2.1. 
Packaging ............................................................................................................. 103 
7.2.2. 
Labeling ................................................................................................................ 103 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ....................................... 104 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................. 104 
7.5. 
STORAGE CONDITIONS .................................................................................................... 104 


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7.6. 
DISPENSING OF TREATMENT ............................................................................................ 104 
7.7. 
TREATMENT REPLACEMENT .............................................................................................. 105 
7.8. 
PROCEDURE FOR BLINDING .............................................................................................. 105 
7.9. 
PROCEDURE FOR UNBLINDING ......................................................................................... 105 
7.10. STUDY DRUG COMPLIANCE ............................................................................................... 106 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................ 106 
7.12. OTHER MEDICATION ........................................................................................................ 106 
7.12.1. 
Handling of concomitant medication ........................................................................ 106 
7.12.2. 
Non-permitted medication (see Table I, APPENDIX III: Permitted/non-permitted 
medication) ........................................................................................................... 107 
7.12.3. 
Permitted medication under condition (see Table II, APPENDIX III: 
Permitted/non-permitted medication) ...................................................................... 107 
7.12.4. 
Permitted medication ............................................................................................. 108 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................. 109 
8.1. 
DEFINITIONS ................................................................................................................... 109 
8.1.1. 
Adverse events ...................................................................................................... 109 
8.1.2. 
Serious adverse events ........................................................................................... 110 
8.1.3. 
Clarification on serious adverse events: .................................................................... 111 
8.1.4. 
Adverse drug reaction ............................................................................................ 112 
8.1.5. 
Unexpected adverse event ...................................................................................... 112 
8.2. 
ASSESSMENTS ................................................................................................................. 112 
8.2.1. 
Intensity assessment .............................................................................................. 112 
8.2.2. 
Relation to the study treatment ............................................................................... 113 
8.2.3. 
Action taken and outcome ...................................................................................... 113 
8.3. 
REPORTING ..................................................................................................................... 114 
8.3.1. 
Reporting an adverse event .................................................................................... 114 
8.3.2. 
Reporting a serious adverse event ........................................................................... 114 
8.3.3. 
Follow-up .............................................................................................................. 116 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 116 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 116 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 117 
8.6.1. 
Pregnancy ............................................................................................................. 117 
8.6.2. 
Medication error..................................................................................................... 117 
8.6.3. 
Misuse .................................................................................................................. 117 
8.6.4. 
Overdose .............................................................................................................. 118 
8.6.5. 
Abuse ................................................................................................................... 118 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 119 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 119 


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9.2. 
ENDPOINTS ..................................................................................................................... 119 
9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 119 
9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 119 
9.2.3. 
Key Secondary Endpoint ......................................................................................... 120 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 120 
9.2.5. 
Exploratory endpoints ............................................................................................. 121 
9.3. 
ANALYSIS SETS ................................................................................................................ 121 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 122 
9.4.1. 
Resolution of NASH ................................................................................................ 122 
9.4.2. 
Long-term endpoints .............................................................................................. 122 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 123 
9.5.1. 
Key secondary endpoint.......................................................................................... 123 
9.5.2. 
Other secondary endpoints ..................................................................................... 123 
9.5.3. 
Subgroup analyses ................................................................................................. 123 
9.5.4. 
Exploratory analyses .............................................................................................. 124 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 124 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 124 
9.7.1. 
Resolution of NASH ................................................................................................ 124 
9.7.2. 
Time to clinical event/death .................................................................................... 125 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 125 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 126 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 126 
10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 127 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 127 
10.2. RETENTION OF RECORDS ................................................................................................. 127 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 129 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 129 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 130 
11.3. QUALITY ASSURANCE ....................................................................................................... 130 
12. 
ETHICS AND REGULATORY................................................................................................ 131 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 131 
12.2. COMPETENT AUTHORITY .................................................................................................. 132 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 132 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 132 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 133 
13. 
FINANCING AND INSURANCE ............................................................................................ 134 
13.1. FINANCIAL ISSUES ........................................................................................................... 134 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 134 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 135 


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14.1. STUDY REPORT ................................................................................................................ 135 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 135 
15. 
REFERENCES LIST ............................................................................................................ 137 
APPENDICES .................................................................................................................................. 140 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 141 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 149 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 150 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 152 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 153 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
35 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
39 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
100 
 
 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
43 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
44 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
AFP 
Alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 


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GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 


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SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 


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proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 


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macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver.  
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
 Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 


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the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
elafibranor (GFT505) has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 


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1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 


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1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 621 volunteers were randomized in 
these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 
volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 


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The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180, and 240 mg of elafibranor, and the time dependency of the PK parameters 
after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 
treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 


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tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 
(-20% to -35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 


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high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C, and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia, and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 
these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 


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resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 


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Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 
fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint).  


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Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 


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in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 
will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 


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2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire) 
• 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed 
in the composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674  patients) 
treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with at least 2 
of the following conditions: persistent elevated (absence of normal ALT within the past year, obesity 
defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education Program’s 
Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also be 
enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 


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• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an 
event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 


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• 
Physical examination (described in Section 6.2.1). 
• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, an additional SV2 visit will be booked at 
least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
Visits SV1 and V1 should be scheduled at least 8 weeks apart in order to have 2 consecutive baseline 
values of AST, ALT, total bilirubin, and INR for DILI adjudication (using SV1 and V1 kits). 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 32, and 33 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 
 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, an additional SV2 visit will be booked by at 
least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood samples for 
coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver biopsy. 
Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), a surrogate endpoint 
analysis will be performed and potentially filed for initial market approval under Subpart H or conditional 
approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 


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• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.5) 
• 
Drug accountability (every visit from V2). 
• 
Ultrasonography of bladder and urinary tract (at V1 and V5 only) (described in Section 6.2.6). 
Additional procedures to be performed at V7 are: 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in ) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, 
death due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 


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3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 
1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
• 
Ultrasonography of bladder and urinary tract (at V8 then every year [V10, V12…]) (described in 
Section 6.2.6). 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the Investigator may 


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decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed 
for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2), 
• 
Urinary pregnancy test (for WOCBP only)  
• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 


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Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
the onset of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
 ascites 
 
hepatorenal syndrome 


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 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to 
Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.11.3. 
Specific monitoring 
If the conditional approval for elafibranor is not obtained upon submission of interim analysis results, 
patients will be asked to come back for a specific monitoring visit every year over 4 years after the end of 
the long term treatment period. 
These specifics visits will include: dosage of alpha-fetoprotein (AFP) and osteocalcin, urine 
cytology, and ultrasonography of urinary tracts and bladder. 
 


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3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, 
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like 
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on 
stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
10. Patients following adequate life style recommendations 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
18. Patients for whom life styles recommendations have never been introduced. 
 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 


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19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. 
Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
24. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
25. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
26. Positive anti-human immunodeficiency virus (HIV) antibody. 
27. AST and/or ALT >10 x upper limit of normal (ULN). 
28. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
29. INR >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
33. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle 
recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 7 days. 
• 
On each study visit day, study treatment will be taken under fasting conditions after the blood 
sampling (which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 


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• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1) 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 


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Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 


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and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 


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5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 
the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site.  
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 
24 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, 
signed, and dated by the Investigator as soon as they are received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 
3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3).  
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). Alfa-fetoprotein and osteocalcin will be tested every year from V1 up to 
end of study (at V1, V5, V8, V10, V12...). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 
6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel to 
the floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 
80% of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the 
LTTP under 2 hour fasting conditions. Where possible, FibroScan must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.  
In case of result ≥14 kPa or of sudden increase from previous measurement, a repeated measurement will 
be required 4 weeks later (to be performed at an unscheduled visit). 
If at baseline, the measurement gives a value ≥14 kPa but without being associated with confirmed 
histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but will not be 
used for the detection of cirrhosis (no repeat test required for patients with baseline≥14 kPa at V1). 
6.2.6. 
Bladder and urinary tract ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year from V1 up to end of study (at 
V1, V5, V8, Vn…). Where possible ultrasonographic exam must be done at the day of visit. Otherwise, it 
can be performed within 7 days around the visit date.   
 
6.2.7. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 


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6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 
3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN.  
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC Charter). 
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 


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• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5: permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study drug and 
schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (calculated NAFLD fibrosis >0.676 score or reported FIB-4 >2.67). 


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In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. A 
detailed description of the interim analysis procedures and decision-making process will be provided in the 
DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 
1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist, all of whom will be 
independent of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 621 volunteers were randomized 
in these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 


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A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety 
of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 69 SAEs that have been reported cumulatively in the clinical development program, 48 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. For all SAEs, the 
treatment code has been broken (end of study unblinding). 
Of the 48 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the investigators (serious adverse reaction). They consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in 
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
For 3 of the cases (atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease) after 
later investigations, given the medical history of the patients or the time of occurrence of the event, 
relationship to elafibranor was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal disorders  
Nausea 
Mild to severe 
4.4% 
Diarrhea  
Mild to moderate 
3.3% 
Vomiting 
Mild to moderate 
1.6% 
General disorders and administration site 
conditions  
Fatigue 
Mild to moderate 
1.9% 
Asthenia  
Mild to moderate 
1.1% 


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System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Investigations  
Hepatic enzymes increased (mainly 
transaminases) 
Mild to severe 
1.8% 
Blood creatine phosphokinase increased 
Mild to moderate 
1.1% 
Musculoskeletal and connective tissue 
disorders  
Myalgia 
Mild to severe 
1.6% 
Metabolism & nutrition disorders  
Decrease appetite 
Mild to severe 
1.6% 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 
1.2% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.2% 
 
Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
based on creatinine). Myalgia, decrease of appetite and hot flush were also reported in more than 1% of 
patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI.  
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014).  
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study between 


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elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods during clinical 
trials should be avoided, and they should be accompanied by barrier methods. 
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as nausea, diarrhea 
and vomiting, and asthenia or fatigue are considered common and expected adverse reactions reasonably 
associated with elafibranor. Most of them are of mild to moderate intensity. As previously, laboratory 
increases of serum creatinine or CPK should be monitored throughout clinical trials as this has been 
observed in Phase II trials, and is a known PPARα agonist effect. Elevation of AT will be monitored as well 
as DILI. In the absence of human pregnancy data, double contraception should be maintained for women 
of childbearing potential participating in clinical trials with elafibranor treatment, up to 1 month after end of 
study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 
objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is to be 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis, every 6 months after Randomization of the first patient. The DSMB will consist of 5 experienced 
physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 
1 statistician, all independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: Product carton and wallet labeling 
 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and 
ensure the study drug is at site for the visits occurring. The IXRS will continue to project study drug 
requirements per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond 
to the number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number 
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available 
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the 
entered treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling 
 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II in 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 


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within 6 months prior to Screening) and information should be communicated to the Medical Monitor in 
order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” 
basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I 
in 
APPENDIX 
III: 
Permitted/non-permitted medication) 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 
weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition (see Table II in APPENDIX III: 
Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
Ursodeoxycholic acid. 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE.  
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 


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not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 


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• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 


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• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 


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Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient. Whenever possible, symptoms 
should be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, 
maximal intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) 
and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall 
pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN 
fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the surrogate efficacy analysis when at least 1023 of the F2 to F3 patients 
complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 for details). 
An additional exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 


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• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the surrogate endpoint analysis (at least 1023 
patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 


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o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 


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Patients in the ITT, FITT, PPS, and exploratory F1 cohorts (study population and efficacy data) will 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 99% confidence interval. The main confirmatory analysis will be performed 
when at least 1023 F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death and time to first 
cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s model, log 
rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 


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Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. The analysis will be performed at the time of the surrogate endpoint 
analysis when at least 1023 of patients with fibrosis stage F2 and F3 have completed the 72 week 
treatment period or discontinued from the study. The null hypothesis will be tested at the two-sided 0.01 
alpha level. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 
data will be analyzed using a nonparametric analysis of covariance method of Zink and Koch.37 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 


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• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the 
primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided 
α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.01. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 


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The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 


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Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics.  
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when 1023 F2 and F3 patients 
complete 72 weeks of treatment or discontinue early from the study. The null hypothesis will be tested at 
the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target 
number of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santibanez C, Haim D, et al. Enhancement in liver nuclear factor-kb (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-
acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. Epub 
2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al. Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
Trials Using Cox Proportional Hazards Models and Nonparametric Randomization Based 
Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
37. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 
.  
 


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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
3.1 France 
DATE: 
April 10th, 2017 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
  
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
ePRO 
 
 
 
 
 
 
 
 


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AMENDMENT 2: 10 APRIL 2017 
Amendment 2 is a non substantial change to clarify the collection of 2 baseline values of liver enzymes before study treatment initiation. This remains in line with the FDA 
request to obtain 2 baseline values of liver transaminase, total bilirubin, and INR at least 8 weeks apart, in order to be able to have 2 baseline values in case of DILI 
adjudication.  Added text is bolded; deleted text is struck through. 
Summary of major changes to the protocol: 
Section 
New Text 
Table 1: 
 STUDY GENERAL 
ASSESSMENT SCHEDULE 
Table 1 updated with changes related to the screening period 
 
 
4. The visits to be performed during the screening period should be scheduled according to  the following requirements:  
 
If there are historical lab values for AST, ALT, total bilirubin and INR that are within 8 weeks to 6 months of the 
planned Randomization visit (V1) these results can be used as the first baseline values in case of DILI 
adjudication. If there are no historical lab values that meet this requirement, then SV1 and V1 must be 
scheduled at least 8 weeks apart. 
 
This The visit SV2 only occurs if no historical biopsy within 6 months before the Screening Visit is available. A screening liver 
biopsy and slides shipment to the central pathologist must be performed at least 4 weeks before Randomization,(in order to 


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Section 
New Text 
obtain the results in time). However, in some exceptional cases, the central reading process can be expedited 
allowing a shorter time between SV1 or SV2 and V1. Coagulation (platelet count and PT [INR]) should be checked locally 
prior to this liver biopsy (according to local medical standards in each hospital). 
 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the 
patients 
 
Table 2: 
STUDY BIOLOGICAL 
ASSESSMENT SCHEDULE 
Table 2 updated with changes related to the screening period 
 
6. If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned 
randomization visit (V1) are available, then SV1 and V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values 
for DILI adjudication. In any case, the visits should be scheduled in order to obtain the needed results prior to the randomization. 
Visits SV1 and V1 should be scheduled at least 8 weeks apart in order to have 2 consecutive baseline values of AST, ALT, total bilirubin, and INR for DILI 
adjudication 
Figure 1:  
STUDY DURATION AND 
VISIT SCHEDULE 
Figure updated with changes related to the screening period 


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Section 
New Text 
 
Figure 2:  
PREGNANCY TESTING 
SCHEDULE FOR WOMEN 
OF CHILDBEARING 
POTENTIAL 
Figure updated with changes related to the screening period 


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Section 
New Text 
 
Section 3.6.1 
3.6 - SCREENING PERIOD (WEEK -12 TO WEEK -1) 
 
3.6.1 - Screening visits SV1 (Week 12 to Week 8) and SV2 (Week 12 to Week 4): 
 
The following screening procedures will be performed for all potential patients at SV1 conducted between during the screening period 
and prior to randomization Week 12 and Week 8 prior to Randomization: 
 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The signature of the informed consent 
may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 


Cli ni c al Tri al G F T 5 0 5 -3 1 5 -1  
 Pr ot o c ol V 3. 1 1 0 A pril 2 0 1 7  
G E N F I T  
C O N FI D E N TI A L  
P a g e 1 3  of 1 4 2  
S e cti o n  
N e w T e xt  
•  
P h ysi c a l e x a mi n ati o n ( d es cri b e d i n S e cti o n 6. 2. 1 ). 
•  
A d e q u at e  di et  r e c o m m e n d ati o ns  ( d es cri b e d  i n  S e cti o n 5. 1. 1  a n d A P P E N DI X  II:  A d e q uat e  di et  a n d  lif est yl e  r e c o m m e n d ati o ns ), 
al c o h ol r estri cti o ns ( d es cri b e d i n S e cti o n  5. 1. 2 ), a n d t o b a c c o h a bits. 
•  
R e c or d vit al si g ns ( d es cri b e d i n S e cti o n  6. 2. 3 ). 
•  
R e c or d h ei g ht, w ei g ht, a n d w aist cir c u mf er e n c e.  
•  
C h e c k  c o n c o mit a nt/ pri or  m e di c ati o n  ( wit hi n  6  m o nt hs  pri or  t o  S cr e e ni n g)  ( d es cri b e d  i n  S e cti o n  7. 1 2  a n d A P P E N DI X  III:  
P er mitt e d/ n o n -p er mitt e d m e di c ati o n ) 
•  
C h e c k  if  a  li v er  bi o ps y  wit h  c o nfir m e d  N A S H  a n d  fi br osis  is  a v ail a bl e,  a n d,  if  s o  s e n d  s a m pl e  f or  c e ntr al  c o nfir m ati o n  of  N A S H 
di a g n osis ( d es cri b e d i n S e cti o n  6. 1. 1. 2 ). T his hist oric al di a g n osti c bi o ps y s h o ul d b e o bt ai n e d wit hi n 6 m o nt hs pri or t o t h e S cr e e ni n g 
Visit.  
•  
C h e c k A Es fr o m ti m e of I nf or m e d C o ns e nt F or m (I C F) si g n at ur e ( d es cri b e d i n S e cti o n  6  a n d S e cti o n  8 ). 
T h e S cr e e ni n g bi ol o gi c al ass ess m e nt ( S B 1 will b e s c h e d ul e d at S V 1).  
If n o di a g n osti c li v er bi o ps y ( wit hi n 6 m o nt hs of S V 1) is a v ail a bl e, it i s r e c o m m e n d e d t o s c h e d ul e a n a d diti o n al S V 2 visit will b e b o o k e d  
at l e ast W e e k -4 ( p eri o d b etw e e n S cr e e ni n g a n d W e e k -4)  pri or t o t h e pl a n n e d R a n d o miz ati o n V 1, i n or d er t o o bt ai n t h e r e s ult s i n 
ti m e.  
 
T h e f oll o wi n g bi ol o gi c al ass ess m e nts ( d et ail e d i n T a bl e 2) will b e p erf or m e d at S B 1:  
 Bl o o d s a m pl es ( d es cri b e d i n T a bl e 2).  
 W h ol e bl o o d, pl as m a & s er u m b a n k s a m pl es ( o nl y if a d diti o n al g e n eti c a n d bi o m ar k er I C F si g n e d).  
 Uri n al ysis di psti c k.  
 Uri n ar y pr e g n a n c y t est (f or w o m e n of c hil d b e ari n g p ot e nti al o nl y [ W O C B P]).  
 
If n o hi st ori c al v al u e s of A S T, A L T, t ot al bilir u bi n a n d I N R m e eti n g t h e r e q uir e m e nt s of wit hi n 8 w e e k s t o 6 m o nt h s of 
r a n d o mi z ati o n vi sit ar e a v ail a bl e, t h e n S V 1 a n d V 1 m u st b e s c h e d ul e d at l e a st 8 w e e k s a p art i n or d er t o h a v e 2 c o n s e c uti v e 
v al u e s f or D I L I a dj u di c ati o n.  
Visits S V 1 a n d V 1 s h o ul d b e s c h e d ul e d at l e ast 8 w e e ks a p art i n or d er t o h a v e 2 c o ns e c uti v e b as eli n e v al u es of A S T, A L T, t ot al bilir u bi n, a n d 
I N R f or DI LI a dj u di c ati o n ( usi n g S V 1 a n d V 1 kits).  


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Section 
New Text 
Section 3.6.2 
3.6.2- Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an additional SV2 visit will be booked by 
at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood samples for coagulation (detailed in Table 2) will be 
taken and tested at a local laboratory prior to the liver biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis 
(described in Section 6.1.1.2).  
 
Section 6.3.2 
6.3.2 -Liver function monitoring  
 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be adjudicated by the Clinical Events 
Committee (CEC; see Section 6.5), as well as all DILI events (see Section 6.5).  
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total bilirubin, and INR 
results meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1), or, using lab results 
from SV1 and V1 that are at least 8 weeks apart. For DILI adjudication, assessment may be performed using as baseline value the 
average obtained from measurements at the SV1 and V1 visits (described in the CEC Charter).  
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to permanent discontinuation of the 
patient from study drug, and scheduling of EOT visit (Section 3.9). 


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Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 
• 
the version number and date were updated throughout the protocol 
• 
The table 2, study biological assessment schedule has been slightly corrected to reflect that the 
parameters for specific monitoring are analyzed by batch . 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
 
Primary objectives – long-term endpoints  
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
Hepatocellular carcinoma 
• 
the onset of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis (SAF) 
activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory objectives 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and NAFLD 
Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 


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o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the tolerability and safety. 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver markers 
o 
renal biomarkers (including urinalysis) 
o 
cardiac biomarkers 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by a 
body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or 
homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement 
for presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is 
confirmed as well as any other event listed in the long-term composite endpoint, patients will be 
discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
• 
674 patients in placebo group  
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~250 centers 
Number of participating countries: ~25 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, 
Mexico, Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week-12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  


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o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented 
ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the patient)  
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
-Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at 
least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, 
and lobular inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of 
normal value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  
o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before Screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation). 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months 
prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7). 
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver 
biopsy until the end of treatment. 
 
10. Patients following adequate life style recommendations 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c 
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal 
HbA1c (HbA1c >9.0%) leads to exclusion. 


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6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or 
positive HCV Ab at Screening) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease  
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic homozygous hemochromatosis 
o 
known or suspected hepatocellular carcinoma (HCC) 
o 
history or planned liver transplant, or current MELD score >12 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
18. Patients for whom life styles recommendations have never been introduced. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, 
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage 
has been kept constant for at least 2 months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
24. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
25. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
26. Positive anti-human immunodeficiency virus antibody. 
27. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN). 


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28. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients 
are allowed into the study. 
29. International normalized ratio >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). 
33. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints  
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 


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o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – March 2017 
• 
Recruitment period: March 2016 – March 2018 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q4 2018 – Q1 2019 
• 
LPLV (LTTP): March 2022 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist all of whom will be 
independent of the participants in the study. 
 
















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4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic and 
biomarker ICF. 
6. 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1) are available, then SV1 and 
V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits should be scheduled in order to obtain the needed 
results prior to the randomization. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
8. 
AFP and osteocalcin to be tested every year (V1, V5, V8, V10, V12, V14...). 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
AMENDMENT 2: 10 APRIL 2017 ........................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 16 
TABLE OF CONTENTS ....................................................................................................................... 33 
TABLE OF TABLES ............................................................................................................................ 39 
TABLE OF FIGURES .......................................................................................................................... 39 
LIST OF ABBREVIATIONS .................................................................................................................. 40 
1. 
INTRODUCTION ................................................................................................................. 43 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 43 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 43 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 45 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 46 
1.4.1. 
Pharmacology .......................................................................................................... 46 
1.4.2. 
Safety pharmacology ................................................................................................ 46 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 46 
1.4.4. 
Toxicology ............................................................................................................... 48 
1.5. 
CLINICAL STUDIES ............................................................................................................. 49 
1.5.1. 
Phase I program ...................................................................................................... 49 
1.5.2. 
Phase II program ..................................................................................................... 50 
1.6. 
CONCLUSION ..................................................................................................................... 52 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 53 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 54 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 54 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 54 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) ............................... 54 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 55 
1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 55 
2. 
TRIAL OBJECTIVES ............................................................................................................. 57 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 57 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 57 


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2.1.2. 
Long-term endpoint ................................................................................................. 57 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS ................................... 57 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 58 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 58 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP ......................................................................... 59 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 59 
3. 
TRIAL DESIGN .................................................................................................................... 60 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 60 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 60 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 61 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 61 
3.5. 
STUDY PERIODS ................................................................................................................. 61 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) ...................................................................... 61 
3.6.1. 
Screening visits SV1 and SV2: ................................................................................... 61 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): ....... 63 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 63 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 63 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 64 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 64 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 65 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 66 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 67 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 67 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 68 
3.11. OPTIONAL VISITS .............................................................................................................. 69 
3.11.1. 
Retesting screening visits .......................................................................................... 69 
3.11.2. 
Unscheduled visits ................................................................................................... 69 
3.11.3. 
Specific monitoring ................................................................................................... 69 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY ................................................................................. 70 
4. 
PATIENT SELECTION .......................................................................................................... 71 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 71 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 72 
5. 
TRIAL PROCEDURES ........................................................................................................... 75 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 75 
5.1.1. 
Standard diet and exercise recommendations ............................................................. 75 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 75 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 76 
5.1.4. 
Sun exposure .......................................................................................................... 76 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 76 


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5.2.1. 
Handling of patient withdrawal .................................................................................. 76 
5.2.2. 
Permanent discontinuations of study drug .................................................................. 76 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 77 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 78 
5.2.5. 
Replacement ........................................................................................................... 78 
5.2.6. 
Premature discontinuation of the study ...................................................................... 78 
5.3. 
PATIENT RESCREENING ...................................................................................................... 79 
6. 
ASSESSMENTS ................................................................................................................... 80 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 80 
6.1.1. 
Histological assessments ........................................................................................... 80 
6.1.2. 
Biological assessments ............................................................................................. 81 
6.1.3. 
Constitution of biobank ............................................................................................. 82 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 83 
6.2.1. 
Physical examination ................................................................................................ 83 
6.2.2. 
Waist circumference ................................................................................................. 83 
6.2.3. 
Vital signs ............................................................................................................... 83 
6.2.4. 
Electrocardiogram .................................................................................................... 84 
6.2.5. 
FibroScan ................................................................................................................ 84 
6.2.6. 
Bladder and urinary tract ultrasonography .................................................................. 84 
6.2.7. 
Quality of life questionnaire ...................................................................................... 84 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 85 
6.3.1. 
Creatine phosphokinase ............................................................................................ 85 
6.3.2. 
Liver function monitoring .......................................................................................... 85 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 86 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 87 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 87 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 87 
6.6.1. 
Summary of safety data............................................................................................ 87 
6.6.2. 
Safety data conclusion .............................................................................................. 90 
6.6.3. 
Benefit/risk assessment ............................................................................................ 90 
7. 
TREATMENTS ..................................................................................................................... 92 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS .............................................................................. 92 
7.2. 
PACKAGING AND LABELING ................................................................................................ 92 
7.2.1. 
Packaging ............................................................................................................... 92 
7.2.2. 
Labeling .................................................................................................................. 92 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ......................................... 93 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 93 
7.5. 
STORAGE CONDITIONS ...................................................................................................... 93 


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7.6. 
DISPENSING OF TREATMENT .............................................................................................. 93 
7.7. 
TREATMENT REPLACEMENT ................................................................................................ 94 
7.8. 
PROCEDURE FOR BLINDING ................................................................................................ 94 
7.9. 
PROCEDURE FOR UNBLINDING ........................................................................................... 94 
7.10. STUDY DRUG COMPLIANCE ................................................................................................. 95 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. .......................................... 95 
7.12. OTHER MEDICATION .......................................................................................................... 95 
7.12.1. 
Handling of concomitant medication .......................................................................... 95 
7.12.2. 
Non-permitted medication (see Table I in APPENDIX III: Permitted/non-permitted 
medication) ............................................................................................................. 96 
7.12.3. 
Permitted medication under condition (see Table II in APPENDIX III: 
Permitted/non-permitted medication) ........................................................................ 96 
7.12.4. 
Permitted medication ............................................................................................... 97 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 98 
8.1. 
DEFINITIONS ..................................................................................................................... 98 
8.1.1. 
Adverse events ........................................................................................................ 98 
8.1.2. 
Serious adverse events ............................................................................................. 99 
8.1.3. 
Clarification on serious adverse events: .................................................................... 100 
8.1.4. 
Adverse drug reaction ............................................................................................ 101 
8.1.5. 
Unexpected adverse event ...................................................................................... 101 
8.2. 
ASSESSMENTS ................................................................................................................. 101 
8.2.1. 
Intensity assessment .............................................................................................. 101 
8.2.2. 
Relation to the study treatment ............................................................................... 102 
8.2.3. 
Action taken and outcome ...................................................................................... 102 
8.3. 
REPORTING ..................................................................................................................... 103 
8.3.1. 
Reporting an adverse event .................................................................................... 103 
8.3.2. 
Reporting a serious adverse event ........................................................................... 103 
8.3.3. 
Follow-up .............................................................................................................. 105 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 105 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 105 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 106 
8.6.1. 
Pregnancy ............................................................................................................. 106 
8.6.2. 
Medication error..................................................................................................... 106 
8.6.3. 
Misuse .................................................................................................................. 106 
8.6.4. 
Overdose .............................................................................................................. 107 
8.6.5. 
Abuse ................................................................................................................... 107 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 108 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 108 


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9.2. 
ENDPOINTS ..................................................................................................................... 108 
9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 108 
9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 108 
9.2.3. 
Key Secondary Endpoint ......................................................................................... 109 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 109 
9.2.5. 
Exploratory endpoints ............................................................................................. 110 
9.3. 
ANALYSIS SETS ................................................................................................................ 110 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 111 
9.4.1. 
Resolution of NASH ................................................................................................ 111 
9.4.2. 
Long-term endpoints .............................................................................................. 111 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 112 
9.5.1. 
Key secondary endpoint.......................................................................................... 112 
9.5.2. 
Other secondary endpoints ..................................................................................... 112 
9.5.3. 
Subgroup analyses ................................................................................................. 112 
9.5.4. 
Exploratory analyses .............................................................................................. 113 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 113 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 113 
9.7.1. 
Resolution of NASH ................................................................................................ 113 
9.7.2. 
Time to clinical event/death .................................................................................... 114 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 114 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 115 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 115 
10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 116 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 116 
10.2. RETENTION OF RECORDS ................................................................................................. 116 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 118 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 118 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 119 
11.3. QUALITY ASSURANCE ....................................................................................................... 119 
12. 
ETHICS AND REGULATORY................................................................................................ 120 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 120 
12.2. COMPETENT AUTHORITY .................................................................................................. 121 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 121 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 121 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 122 
13. 
FINANCING AND INSURANCE ............................................................................................ 123 
13.1. FINANCIAL ISSUES ........................................................................................................... 123 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 123 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 124 


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14.1. STUDY REPORT ................................................................................................................ 124 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 124 
15. 
REFERENCES LIST ............................................................................................................ 126 
APPENDICES .................................................................................................................................. 129 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 130 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 138 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 139 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 141 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 142 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
23 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
27 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
88 
 
 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
31 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
32 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
AFP 
Alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 


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GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 


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SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 


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proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 


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macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver.  
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
 Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 


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the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
elafibranor (GFT505) has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 


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1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 


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1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 621 volunteers were randomized in 
these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 
volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 


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The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180, and 240 mg of elafibranor, and the time dependency of the PK parameters 
after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 
treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 


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tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 
(-20% to -35%), reduction in low-density-lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 


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high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C, and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia, and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 
these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 


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resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 


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Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 
fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint).  


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Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 


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in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 
will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan® 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 


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2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
• 
To explore the following endpoints in F1 patients in the exploratory group at Week 72 and at the 
end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire) 
• 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis.  
 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed 
in the composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674  patients) 
treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with at least 2 
of the following conditions: persistent elevated (absence of normal ALT within the past year, obesity 
defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education Program’s 
Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also be 
enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 


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• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an 
event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) 
3.6.1. 
Screening visits SV1 and SV2: 
The following screening procedures will be performed for all potential patients at SV1 conducted during the 
screening period and prior to Randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 
• 
Physical examination (described in Section 6.2.1). 


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• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an 
additional SV2 visit at least Week -4 prior to the planned Randomization V1 in order to obtain the results in 
time. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 
months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart in 
order to have 2 consecutive values for DILI adjudication.  
 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 32, and 33 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 


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 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 
A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended 
Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an 
additional SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 


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During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 
At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), a surrogate endpoint 
analysis will be performed and potentially filed for initial market approval under Subpart H or conditional 
approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 


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• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.5) 
• 
Drug accountability (every visit from V2). 
• 
Ultrasonography of bladder and urinary tract (at V1 and V5 only) (described in Section 6.2.6). 
Additional procedures to be performed at V7 are: 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in ) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, 
death due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 


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At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 
1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
• 
Ultrasonography of bladder and urinary tract (at V8 then every year [V10, V12…]) (described in 
Section 6.2.6). 


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3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the Investigator may 
decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed 
for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.6) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2), 
• 
Urinary pregnancy test (for WOCBP only)  


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• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 


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o 
the onset of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
 ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to 
Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.11.3. 
Specific monitoring 
If the conditional approval for elafibranor is not obtained upon submission of interim analysis results, 
patients will be asked to come back for a specific monitoring visit every year over 4 years after the end of 
the long term treatment period. 


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These specifics visits will include: dosage of alpha-fetoprotein (AFP) and osteocalcin, urine 
cytology, and ultrasonography of urinary tracts and bladder. 
 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization.  
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic 
liver biopsy is required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, 
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like 
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on 
stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
10. Patients following adequate life style recommendations 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
18. Patients for whom life styles recommendations have never been introduced. 
 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 


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19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. 
Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
24. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
25. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
26. Positive anti-human immunodeficiency virus (HIV) antibody. 
27. AST and/or ALT >10 x upper limit of normal (ULN). 
28. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
29. INR >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
33. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle 
recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 7 days. 
• 
On each study visit day, study treatment will be taken under fasting conditions after the blood 
sampling (which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 


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• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1) 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 


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Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 


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and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 


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5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 
the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site.  
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 
24 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, 
signed, and dated by the Investigator as soon as they are received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 
3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3).  
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). Alfa-fetoprotein and osteocalcin will be tested every year from V1 up to 
end of study (at V1, V5, V8, V10, V12...). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 
6.2.2. Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel to 
the floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 
80% of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the 
LTTP under 2 hour fasting conditions. Where possible, FibroScan must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date.  
In case of result ≥14 kPa or of sudden increase from previous measurement, a repeated measurement will 
be required 4 weeks later (to be performed at an unscheduled visit). 
If at baseline, the measurement gives a value ≥14 kPa but without being associated with confirmed 
histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but will not be 
used for the detection of cirrhosis (no repeat test required for patients with baseline≥14 kPa at V1). 
6.2.6. 
Bladder and urinary tract ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year from V1 up to end of study (at 
V1, V5, V8, Vn…). Where possible ultrasonographic exam must be done at the day of visit. Otherwise, it 
can be performed within 7 days around the visit date.   
 
6.2.7. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 


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6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 
3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN.  
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned 
randomization visit (V1), or, using lab results from SV1 and V1 that are at least 8 weeks apart. 
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once 
a week) 


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o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5: permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study drug and 
schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%): permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 


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is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (calculated NAFLD fibrosis >0.676 score or reported FIB-4 >2.67). 
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. A 
detailed description of the interim analysis procedures and decision-making process will be provided in the 
DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 
1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist, all of whom will be 
independent of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 621 volunteers were randomized 


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in these studies performed in Phase I centers, including 549 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety 
of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 69 SAEs that have been reported cumulatively in the clinical development program, 48 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. For all SAEs, the 
treatment code has been broken (end of study unblinding). 
Of the 48 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the investigators (serious adverse reaction). They consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in 
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
For 3 of the cases (atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease) after 
later investigations, given the medical history of the patients or the time of occurrence of the event, 
relationship to elafibranor was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal disorders  
Nausea 
Mild to severe 
4.4% 
Diarrhea  
Mild to moderate 
3.3% 
Vomiting 
Mild to moderate 
1.6% 


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System Organ Class 
Adverse Reaction 
Severity 
Frequency 
General disorders and administration site 
conditions  
Fatigue 
Mild to moderate 
1.9% 
Asthenia  
Mild to moderate 
1.1% 
Investigations  
Hepatic enzymes increased (mainly 
transaminases) 
Mild to severe 
1.8% 
Blood creatine phosphokinase increased 
Mild to moderate 
1.1% 
Musculoskeletal and connective tissue 
disorders  
Myalgia 
Mild to severe 
1.6% 
Metabolism & nutrition disorders  
Decrease appetite 
Mild to severe 
1.6% 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 
1.2% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.2% 
 
Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
based on creatinine). Myalgia, decrease of appetite and hot flush were also reported in more than 1% of 
patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials.  
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI.  
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014)34.  
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 


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stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study between 
elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods during clinical 
trials should be avoided, and they should be accompanied by barrier methods. 
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as nausea, diarrhea 
and vomiting, and asthenia or fatigue are considered common and expected adverse reactions reasonably 
associated with elafibranor. Most of them are of mild to moderate intensity. As previously, laboratory 
increases of serum creatinine or CPK should be monitored throughout clinical trials as this has been 
observed in Phase II trials, and is a known PPARα agonist effect. Elevation of AT will be monitored as well 
as DILI. In the absence of human pregnancy data, double contraception should be maintained for women 
of childbearing potential participating in clinical trials with elafibranor treatment, up to 1 month after end of 
study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 
objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is to be 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis, every 6 months after Randomization of the first patient. The DSMB will consist of 5 experienced 
physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 
1 statistician, all independent of the participants in the study.  


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In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: Product carton and wallet labeling 
 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and 
ensure the study drug is at site for the visits occurring. The IXRS will continue to project study drug 
requirements per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond 
to the number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number 
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available 
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the 
entered treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling 
 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II in 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 


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within 6 months prior to Screening) and information should be communicated to the Medical Monitor in 
order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” 
basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I 
in 
APPENDIX 
III: 
Permitted/non-permitted medication) 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 
weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition (see Table II in APPENDIX III: 
Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
Ursodeoxycholic acid. 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE.  
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 


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not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 


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• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 


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• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 


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Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient. Whenever possible, symptoms 
should be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, 
maximal intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) 
and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall 
pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN 
fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the surrogate efficacy analysis when at least 1023 of the F2 to F3 patients 
complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 for details). 
An additional exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 


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• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the surrogate endpoint analysis (at least 1023 
patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring  
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal 
inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 


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o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 


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Patients in the ITT, FITT, PPS, and exploratory F1 cohorts (study population and efficacy data) will 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 99% confidence interval. The main confirmatory analysis will be performed 
when at least 1023 F2/F3 patients have completed the 72 week treatment period or discontinued from the 
study. The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death and time to first 
cardiovascular event death will also analyzed using an unadjusted Cox-proportional hazard’s model, log 
rank test and a nonparametric randomization based analysis of covariance method proposed by Saville and 
Koch.36 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 


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Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. The analysis will be performed at the time of the surrogate endpoint 
analysis when at least 1023 of patients with fibrosis stage F2 and F3 have completed the 72 week 
treatment period or discontinued from the study. The null hypothesis will be tested at the two-sided 0.01 
alpha level. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 
data will be analyzed using a nonparametric analysis of covariance method of Zink and Koch.37 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 


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• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the 
primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided 
α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.01. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 


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The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 


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Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics.  
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when 1023 F2 and F3 patients 
complete 72 weeks of treatment or discontinue early from the study. The null hypothesis will be tested at 
the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target 
number of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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36. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
Trials Using Cox Proportional Hazards Models and Nonparametric Randomization Based 
Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
37. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 
.  
 


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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 






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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
Protocol N°: 
 
GFT505-315-1 / EudraCT N° 2015-005385-38/ IND n°115028 
Version number: 
4.1 France 
Release date:  
03 January 2020 
TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis 
In signing below, I give agreement to the protocol. 
 
______________ 
 
_____ 
Signature 
Date (dd-mmm-yyyy) 






Clinical Trial GFT505-315-1 
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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number: 
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
III 
VERSION: 
4.1 France 
DATE: 
03 January 2020 
SPONSOR: 
GENFIT 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS - France 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
INSTITUTION NAME: 
_______________________________________ 
INSTITUTION ADDRESS: 
_______________________________________ 
_______________________________________ 
SIGNATURE: 
_______________________________________ 
DATE: 
_____ /_______ /________ 
Day 
Month 
Year 






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AMENDMENT 3: 2020 
Amendment 3 is a substantial change to address the addition of a key secondary objective at the surrogate endpoint analysis. Some metabolic endpoints (triglycerides, 
Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c [in diabetic patients], HOMA-IR [in non-diabetic patients]) are upgraded as key secondary endpoints that 
results in addition of a gatekeeping procedure to control the overall type I error rate at a two-sided alpha level of 0.01.  
Furthermore, to be consistent with the Statistical Analysis Plan (SAP), some updates and clarifications are made in the “Statistical Methods and Data Analysis” section.  
Other updates to clarify the FibroScan assessments and the rules of discontinuation related to the liver function monitoring were added. The summary of the safety data 
was also updated to reflect the update of the effective Investigator’s Brochure with no changes to the benefit/risk assessment to the medicinal product. 
Added text is bolded; deleted text is struck through. 
 
 
Summary of major changes to the protocol: 
Section 
New Text 
Section 2 
2 TRIAL OBJECTIVES 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
Section 2.2 
2.2 KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on the following 
endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c 
(in diabetic patients), HOMA-IR (in non-diabetic patients) 


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Section 
New Text 
Section 2.3 
2.3 OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the following 
endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 


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Section 
New Text 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 point 
improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, hepatic 
ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess histological changes after 72 weeks of treatment and follow up biopsy on the following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow up biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN scoring: total 
NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis activity fibrosis (SAF) activity score 
o 
mean changes in NAS, steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity 
score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 


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Section 
New Text 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
o 
To assess the onset to:histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
Section 2.5 
2.5 EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION (WHATEVER THE FIBROSIS 
STAGE – F1, F2 OR F3) 
• 
To explore the following endpoints , in F1 patients and in the overall population whatever the fibrosis stage 
(F1, F2 or F3), the same endpoints as for the primary and secondary objectives.exploratory group at Week 
72 and at the end of the LTTP: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, lobular inflammation, 
or portal inflammation 


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Section 
New Text 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS, fibrosis (using NASH CRN or NAFLD Ishak scoring system), steatosis, hepatic 
ballooning, lobular inflammation, portal inflammation, and SAF activity score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the LTTP: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF 36 questionnaire) 
• 
To assess the tolerability and safety. 
Section 9.2.1 
9.2.1 Surrogate endpoint – resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 72 weeks of treatment. 
Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) and disappearance or persistence of minimal 
lobular inflammation (i.e., grade 0 or 1) with an overall pattern of injury not qualifying for steatohepatitis. Worsening of 
fibrosis is evaluated using NASH CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate 
endpoint will be formally assessed at the time of the surrogate efficacy analysis when at least the first 1023 of 


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Section 
New Text 
therandomized F2 toand F3 patients complete the 72 week treatment period or discontinue early from the study 
treatment (see Section 9.8.1 for details). An additional exploratory analysis of this endpoint will take place at the time of 
the final analysis. 
Section 9.2.3 
9.2.3 Key Secondary Endpoints 
The key secondary endpoint isendpoints are: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 weeks. 
ThisTo assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL 
cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
These key secondary endpoints will be assessed at the time of the surrogate endpoint analysis (at least the first 1023 
randomized patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening of fibrosis endpoint. 
Section 9.2.4 
9.2.4 Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsyat the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow up biopsyat the end 
of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring (at 
the end of LTTP) 


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Section 
New Text 
o 
percentage of patients with at least 1 point improvement in of fibrosis of at least 1 stage according to 
NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN scoring: 
total NAS, [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic 
ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in SAFdisease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
mean percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, hepatic 
ballooning, lobular inflammation, portal inflammation, and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 


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Section 
New Text 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
Section 9.3 
9.3 Analysis Sets 
The following analysis sets will be used in this study: 
•Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
•ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main analysis of the primary 
and key secondary endpoints will be based on the ITT. 
•Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This set will be used to 
summarize safety. 
•Efficacy evaluable set (EES): All F2 and F3 patients in the ITT population who have taken at least one 
dose of study treatment and have a reliable liver biopsy at both baseline and at the end of the 72 week 
treatment period. 


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Section 
New Text 
•Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not have any important 
protocol deviations leading to exclusion from the PPS. Important protocol deviations will be defined in the SAP and 
agreed prior to database lock. Supportive analysis of the primary and key secondary endpoints will be based on the 
PPS.  
•Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
•Full Intent-To-Treat Set (FITT): all randomized patients.  
•Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
Patients in the ITT, FITT, EES, PPS, and exploratory F1 cohorts (study population and efficacy data) will be analyzed based 
on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) will be analyzed based on actual 
treatment received. 
Section 9.4.1 
9.4.1 Resolution of NASH 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of the 72 week 
treatment period will be summarized by treatment group. The main analysis will be performed using a logistic regression 
model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, female), fibrosis stage (F2, F3) and baseline 
NAS. The According to the method described in Ge et al. (2011), the statistical model will be used to 
calculateestimate the odds ratiodifference (elafibranor/placebo) in rate of resolution of NASH without worsening 
of fibrosis and its 99% confidence interval.CI. The main confirmatory analysis will be performed when at least the first 
1023 randomized F2/F3 patients have completed the 72 week treatment period or discontinued from the study treatment. 
The main analysis will be based on the ITT. Supportive analysis will be based on the EES and PPS. 


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Section 
New Text 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a nonresponder for the 
main analysis. Additional sensitivity analysisSupplementary analyses using multiple imputations and a pattern mixture 
model will be performed, as well as sensitivity analysis using a Cochran-Mantel-Haenszel test. Further details will 
be provided in the SAP. 
Section 9.5.1 
9.5.1 Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at the end of the 72 
week treatment period will be summarized separately by treatment group. The data will be analyzed using a logistic 
regression model, with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage and baseline NAS by NASH CRN 
scoring. The analysis will be performed at the time of the surrogate endpoint analysis when at least the first 1023 
ofrandomized patients with fibrosis stage F2 and F3 have completed the 72 week treatment period or discontinued from 
the study treatment. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant. A gatekeeping procedure will be constructed to control the overall Type I error rate for testing 
the key secondary efficacy endpoints at an overall two-sided alpha level of 0.01.  
The main analysis will be based on the IIT. Supportive analyses will be based on the EES and PPS. 
Section 9.5.2 
9.5.2 Other secondary endpoints 
Time to event endpoints such as time to first cardiovascular event/death will be analyzed using the Cox proportional 
hazard’s model in the same manner as time to clinical event/death.  


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Section 
New Text 
Continuous endpoints will be analyzed using an repeated measures Analysis of Covariance (ANCOVA) model with fixed 
terms for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS, and time-point and treatment by time-
point interaction. An unstructured compound symmetry covariance matrix will be used for this analysis. The statistical 
model will be used to calculate the mean treatment difference and 95% confidence interval. If the data does not meet the 
required assumptions for parametric tests, the data will be analyzed using a nonparametric analysis of covariance method 
of Zink and Koch41. 
Section 9.5.3 
9.5.3 Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, including, but not 
limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 
• 
PNPLA3 (absence or presence of risk allele G [i.e. CC vs GG/CG], and within the at risk group, 
homozygous vs. heterozygous for the risk allel G [i.e. CG vs GG]) 
• 
Patients under statins (yes/no), defined as patients who have duration of IP exposure greater or equal 
to 60 days, with extent of exposure to statin greater than or equal to 30 days before the visit 7 biopsy 
date.  


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Section 
New Text 
Section 9.6 
9.6 STRATEGIES TO CONTROL TYPE I ERROR 
A hierarchical gate keeping strategy will be used to control for multiplicity for the The key secondary endpoint. If the 
resolution of NASH without worsening of fibrosisefficacy endpoints will be tested only if the primary surrogate 
endpoint is statistically significant, at a two-sided 1% significance level. A gatekeeping procedure will be 
constructed to control the overall Type I error rate for testing the key secondary endpoint, improvementefficacy 
endpoints at an overall two-sided alpha level of fibrosis according to NASH CRN scoring,0.01. 
The gatekeeping procedure will be tdestailed in a confirmatory mannerthe SAP and set up using the general 
method for building multi-stage parallel gatekeeping procedures in multiplicity problems with a two sided 
α=0.01.several families of null hypotheses (Dmitrienko and Tamhane, 2011, 2013). 
Section 9.7.2 
9.7.2 Time to clinical event/death 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver fibrosis. In the 72-week 
FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an approximate annual drop-out rate of 4%. Based 
on these assumptions, 456 events are required to provide 80% power to show that elafibranor is superior to placebo with 
respect to time to clinical event/death. In order to obtain 456 events, at least 2022 patients will be required in the IIT. 
The number of patients to be enrolled may be adjusted during the course of the study in a blinded manner to 
achieve the desired number of primary events.  This will be accomplished using standard event forecasting 
methods (Anisimov, 2011). 
Section 9.8.1 
9.8.1 Surrogate endpoint analysis 


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Section 
New Text 
The analysis of resolution of NASH without worsening of fibrosis will occur when at least the first 1023 randomized F2 and 
F3 patients complete 72 weeks of treatment or discontinue early from the study treatment. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or conditional 
approval submission. This analysis will be done by an unblinded team separate from the study team; the study team will not 
be unblinded until the final analysis at the end of follow-up. A Data integrity plan will be set-up to detail the blinding 
process and address how data will be published in view of marketing authorization and how integrity of the 
trial will be protected. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study participants. These safety 
reviews will be based on reports generated by the SAC and may One dedicated meeting will be held upon availability 
of the surrogate endpoint analysis results and DSMB will be provided with data summaries that will include 
selected efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not considered 
a formal interim analysis, and no type I error adjustments will be done for these reviews. Details will be in the DSMB Charter. 


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Summary of minor changes to the protocol: 
The following minor changes were made to the protocol. The changes do not impact the reliability of the 
data generated in the clinical trial or the safety or rights of the subjects: 
- 
Study contact details have been updated for one of the Steering Committee members, for the sponsor 
representative, and several vendors representatives 
- 
The version number and date were updated throughout the protocol 
- 
The list of abbreviations has been updated 
- 
Sections "Number of estimated randomized F2-F3 Patients" and "Study Duration (planned)" of the 
synopsis were updated. Appropriate sections of the core protocol were also updated to reflect the 
changes. 
- 
The “Section 1.5 - Clinical Studies” was updated to issue synthetic Clinical Studies summaries reflecting 
the updates of the effective version of the Investigator’s Brochure. 
- 
The "Section 1.6 - Conclusion " was updated to reflect the updates of the effective version of the 
Investigator’s Brochure. 
- 
The “Section 6.2.5 - Fibroscan” was clarified for the assessment conditions. 
- 
The “Section 6.3.2.1 - Monitoring of patients with normal baseline aminotransferase values” and the 
“Section 6.3.2.2 - Monitoring of patients with increased baseline aminotransferase values” were updated 
to clarify the conditions of the associated parameters “INR” and “eosinophilia”. 
- 
The "Section 6.3.3 - Threshold for diagnosis of cirrhosis" was updated for liver biopsy consideration 
- 
The “Section 6.6 - Guidances for Investigators” was updated to reflect the updates of the effective 
version of the Investigator’s Brochure. 
- 
The section 7.4 has been very slightly clarified 
- 
The section 9.5.4 has been updated to include the FITT 
 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with 
fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on 
the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by 
a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, all-cause mortality, and 
liver-related clinical outcomes as measured by the onset of any of the listed adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
 
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
Hepatocellular carcinoma 
• 
the onset of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 


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Key secondary objectives (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c 
(in diabetic patients), HOMA-IR (in non-diabetic patients) 
 
Other secondary objectives: 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH 
CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), 
or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 
point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire) 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
 
 


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Exploratory objectives 
•
To constitute a biobank for discovery and validation of biomarkers in NASH.
Exploratory objectives for F1 group and the overall population (whatever the fibrosis stage – F1, F2 or F3) 
•
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or F3),
the same endpoints as for the primary and secondary objectives
Safety secondary objectives 
•
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg:
o
serious adverse events, adverse events, physical examination, vital signs, medical history,
electrocardiogram
o
hematological parameters
o
liver markers
o
renal biomarkers (including urinalysis)
o
cardiac biomarkers
o
metabolic parameters
o
other biochemical safety markers.
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening Period) 
with: 
•
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration
scored 0-2, and lobular inflammation scored 0-3).
•
NAS ≥4.
•
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine aminotransferase
(ALT; absence of normal value of ALT within the past year), obesity defined by a body mass index
(BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or homeostasis model
assessment of insulin resistance (HOMA-IR) >6.
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement for 
presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is confirmed 
as well as any other event listed in the long-term composite endpoint, patients will be discontinued from 
study. 
Number of estimated randomized F2-F3 Patients: at least 2022 patients (ratio 2:1) 
•
674 patients in placebo group
•
1348 patients in elafibranor (GFT505) group
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~270 centers 
Number of participating countries: ~24 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, Mexico, 
Colombia,  Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 96 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
•
Screening Period: Week-12 to Week -1 prior to Randomization.
•
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or placebo
for 72 weeks.
•
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor
(GFT505) or placebo (until occurrence of prespecified number of events).
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1.
Males or females aged from 18 to 75 years inclusive at first Screening Visit.


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2.
Must provide signed written informed consent and agree to comply with the study protocol.
3.
Females participating in this study must be of non-childbearing potential or using highly efficient
contraception for the full duration of the study and for 1 month after the end of treatment, as
described below:
o
Cessation of menses for at least 12 months due to ovarian failure,
o
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented
ovarian failure
o
If requested by local IRB regulations and/or National laws, sexual abstinence may be
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of the patient)
o
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion,
vasectomized partner, or intra-uterine device)
o
Double contraception with barrier AND highly effective hormonal method of contraception
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal
contraception associated with inhibition of ovulation; oral, injectable, or implantable
progestogen-only hormonal contraception associated with inhibition of ovulation; or
intrauterine hormone-releasing system). The hormonal contraception must be started at least
1 month prior to Randomization.
4.
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1
in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular
inflammation scored 0-3).
5.
NAS ≥4.
6.
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal
value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III
definition), type 2 diabetes, or HOMA-IR >6.
7.
Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
o
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy within
6 months before Screening is available)
o
1 liver biopsy after 72 weeks of treatment for assessment of the treatment effects on NASH
o
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has
already been performed within the past year
o
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological
confirmation).
8.
If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic
liver biopsy is required.
9.
For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic
drugs, change in anti-diabetic therapy must follow these requirements:
o
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e.,
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins,
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-
1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months prior
to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose in the
6 months prior to diagnostic liver biopsy.
o
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment (V7).
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until 
the end of treatment. 
10. Patients following adequate life style recommendations.
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1.
Known chronic heart failure (Grade I to IV of New York Heart Association classification).
2.
History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in
the course of the study.
3.
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.


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4.
Type 1 diabetes patients.
5.
Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal
HbA1c (HbA1c >9.0%) leads to exclusion.
6.
Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was
discontinued at least 6 months before the diagnostic liver biopsy.
7.
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial
infarction, revascularization procedures).
8.
Weight loss of more than 5% within 6 months prior to Randomization.
9.
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis).
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system
are excluded.
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically
defined as higher than 20 g pure alcohol per day.
11. Pregnant or lactating females or females planning to become pregnant during the study period.
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures
including, but not restricted to:
o
positive hepatitis B surface antigen
o
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or
positive HCV Ab at Screening)
o
suspicion of drug-induced liver disease
o
alcoholic liver disease
o
autoimmune hepatitis
o
Wilson’s disease
o
primary biliary cirrhosis, primary sclerosing cholangitis
o
genetic homozygous hemochromatosis
o
known or suspected hepatocellular carcinoma (HCC)
o
history or planned liver transplant, or current MELD score >12
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with
the recommendations of National Law in force applicable to clinical trials.
14. Patients who cannot be contacted in case of emergency.
15. Known hypersensitivity to the investigation product or any of its formulation excipients.
16. Patients with previous exposure to elafibranor.
17. Patients who are currently participating in, plan to participate in, or have participated in an
investigational drug trial or medical device trial containing active substance within 30 days or five
half-lives, whichever is longer, prior to Screening.
18. Patients for whom life styles recommendations have never been introduced.
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe,
or other nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept
constant for at least 2 months prior to Screening.
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to:
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to
Screening and up to end of treatment.
21. Currently taking any medication that could interfere with study medication absorption, distribution,
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g.,
indomethacin, which are not permitted from Randomization until end of treatment.
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known
cancers.
23. Patients with any history of cancer are excluded except patients with basal cell carcinoma.
24. Evidence of any other unstable or untreated clinically significant immunological, endocrine,
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease.


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25. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant
with the study is uncertain.
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
26. Positive anti-human immunodeficiency virus antibody.
27. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN).
28. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients are
allowed into the study.
29. International normalized ratio >1.40 due to altered hepatic function.
30. Platelet count <100,000/mm3 due to portal hypertension.
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females.
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 60
ml/min/1.73 m2).
33. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion.
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
•
liver transplantation
•
MELD score ≥15
•
HCC
•
the onset of:
o
variceal bleed
o
hepatic encephalopathy
o
spontaneous bacterial peritonitis
o
ascites
o
hepatorenal syndrome
o
hepatopulmonary syndrome
o
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that
these lead to hospitalization or transfusion).
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 96 months after the first patient is randomized. 
Key secondary endpoints (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 
weeks. 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
Other secondary endpoints 
•
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the
following endpoints:
o
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of
LTTP)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH
CRN scoring (at the end of LTTP)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH
CRN scoring without worsening of NASH
o
percentage of patients with no worsening of fibrosis and no worsening of NASH
o
percentage of patients with resolution of NASH and improvement of Fibrosis


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o
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis,
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal
inflammation
o
percentage of patients with improvement of NAS of at least 2 points
o
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point
improvement in hepatic ballooning
o
percentage of patients with at least a 1 point improvement in disease activity score (sum of
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring
o
percentage of patients with at least a 1 point improvement in disease activity score (sum of
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1
point improvement in hepatic ballooning
o
percentage of patients with at least a 1 point improvement in disease activity score (sum of
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF)
scoring and with at least 1 point improvement in hepatic ballooning
o
percentage of patients with at least 2 points improvement in disease activity score according
to NAS scoring and SAF scoring
o
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis,
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score
o
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry.
•
To assess the following endpoints at Week 72, and at the end of the LTTP:
o
changes in liver enzymes and liver markers
o
changes in noninvasive markers of fibrosis and steatosis
o
changes in lipid parameters
o
variation in body weight
o
changes in insulin resistance and glucose homeostasis markers
o
changes in inflammatory markers
o
changes in cardiovascular risk profile as assessed by Framingham scores
o
changes in liver stiffness by Fibroscan measurement
o
changes in quality of life (SF-36 questionnaire).
•
To assess the onset of:
o
histological liver cirrhosis
o
death of any cause
o
any portal hypertension or cirrhosis related events
o
cardiovascular events
o
liver-related death events.
Exploratory endpoints 
•
To constitute a biobank for discovery and validation of biomarkers in NASH.
Study Duration (planned): estimated 96 months (First Patient First Visit [FPFV]-Last Patient Last Visit [LPLV]) 
•
Regulatory/ethics committee submission: January 2016
•
Initiation visits: March 2016 – Sep 2018
•
Recruitment period: March 2016 – May 2020
•
FPFV: March 2016
•
Surrogate endpoint analysis: Q1 2020 – Q2 2020
•
LPLV (LTTP): estimated within Q1 2024
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a safety 
data review on a regular basis during the trial to protect patient welfare and preserve study integrity. The 
DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 


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Clinical Events Committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (except for histological cirrhosis), all Drug-Induced Liver Injury events, and all 
Major Cardiovascular Events as defined in the CEC charter. The CEC assessment and adjudication will occur 
in a blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist all of whom will be 
independent of the participants in the study. 
 








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 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the patients. 
5. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to Randomization 
Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact requires 
a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having permanently 
discontinued study drug but remaining in the study (Same information collected except IP compliance control). 
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. In the LTTP the first ECG will be performed at V9 and then every 48 weeks. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively), 
and every 48 weeks thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 
14. Ultrasonographic exam will be performed at V1 then approximately every year (at V5, V8, V10, V12…). Where possible ultrasonographic exam must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date. 








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4. 
 CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic and biomarker 
ICF. 
6. 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned Randomization visit (V1) are available, then SV1 and 
V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits should be scheduled in order to obtain the needed 
results prior to the randomization. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
8. 
AFP and osteocalcin to be tested every year (V1, V5, V8, V10, V12, V14...). 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
AMENDMENT 3: 2020 ......................................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 23 
TABLE OF CONTENTS ....................................................................................................................... 41 
TABLE OF TABLES ............................................................................................................................ 47 
TABLE OF FIGURES .......................................................................................................................... 48 
LIST OF ABBREVIATIONS .................................................................................................................. 49 
1. 
INTRODUCTION ................................................................................................................. 52 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 52 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 52 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 54 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 55 
1.4.1. 
Pharmacology .......................................................................................................... 55 
1.4.2. 
Safety pharmacology ................................................................................................ 55 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 55 
1.4.4. 
Toxicology ............................................................................................................... 56 
1.4.4.1. 
Mutagenicity and genotoxicity ..................................................................................................... 56 
1.4.4.2. 
Acute toxicity .................................................................................................................................. 57 
1.4.4.3. 
Repeated dose toxicity studies .................................................................................................... 57 
1.4.4.4. 
Phototoxicity studies ..................................................................................................................... 57 
1.5. 
CLINICAL STUDIES ............................................................................................................. 57 
1.5.1. 
NASH ...................................................................................................................... 57 
1.5.2. 
Primary Biliary Cholangitis (PBC) ............................................................................... 58 
1.6. 
CONCLUSION ..................................................................................................................... 59 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 59 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 60 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 60 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 60 
1.9.2. 
Primary endpoint for clinical outcome (post-approval confirmation) .............................. 61 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 61 


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1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 62 
2. 
TRIAL OBJECTIVES ............................................................................................................. 64 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 64 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 64 
2.1.2. 
Long-term endpoint ................................................................................................. 64 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS .................................. 64 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 65 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 66 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION (WHATEVER THE 
FIBROSIS STAGE – F1, F2 OR F3) ........................................................................................ 66 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 66 
3. 
TRIAL DESIGN .................................................................................................................... 67 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 67 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 67 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 68 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 68 
3.5. 
STUDY PERIODS ................................................................................................................. 68 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) ...................................................................... 68 
3.6.1. 
Screening visits SV1 and SV2: ................................................................................... 68 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): ....... 70 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 70 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 70 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 71 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 71 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 72 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 73 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 74 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 74 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 75 
3.11. OPTIONAL VISITS .............................................................................................................. 76 
3.11.1. 
Retesting screening visits .......................................................................................... 76 
3.11.2. 
Unscheduled visits ................................................................................................... 76 
3.11.3. 
Specific monitoring ................................................................................................... 76 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY ................................................................................. 77 
4. 
PATIENT SELECTION .......................................................................................................... 78 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 78 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 79 
5. 
TRIAL PROCEDURES ........................................................................................................... 82 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 82 


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5.1.1. 
Standard diet and exercise recommendations ............................................................. 82 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 82 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 83 
5.1.4. 
Sun exposure .......................................................................................................... 83 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 83 
5.2.1. 
Handling of patient withdrawal .................................................................................. 83 
5.2.2. 
Permanent discontinuations of study drug .................................................................. 83 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 84 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 85 
5.2.5. 
Replacement ........................................................................................................... 85 
5.2.6. 
Premature discontinuation of the study ...................................................................... 85 
5.3. 
PATIENT RESCREENING ...................................................................................................... 85 
6. 
ASSESSMENTS ................................................................................................................... 87 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 87 
6.1.1. 
Histological assessments ........................................................................................... 87 
6.1.1.1. 
Recommendations related to liver biopsy .................................................................................. 87 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score .................................................... 88 
6.1.2. 
Biological assessments ............................................................................................. 88 
6.1.2.1. 
Laboratory assessments ............................................................................................................... 89 
6.1.2.2. 
Urinary pregnancy tests ................................................................................................................ 89 
6.1.2.3. 
Serology (SB1) ............................................................................................................................... 89 
6.1.2.4. 
Other parameters .......................................................................................................................... 89 
6.1.3. 
Constitution of biobank ............................................................................................. 89 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 90 
6.2.1. 
Physical examination ................................................................................................ 90 
6.2.2. 
Waist circumference ................................................................................................. 90 
6.2.3. 
Vital signs ............................................................................................................... 90 
6.2.3.1. 
Important points for clinical blood pressure measurement ..................................................... 90 
6.2.4. 
Electrocardiogram .................................................................................................... 91 
6.2.5. 
FibroScan ................................................................................................................ 91 
6.2.6. 
Quality of life questionnaire ...................................................................................... 91 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 92 
6.3.1. 
Creatine phosphokinase ............................................................................................ 92 
6.3.2. 
Liver function monitoring .......................................................................................... 92 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values .................................. 92 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values ............................. 93 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 94 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 94 


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6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 94 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 95 
6.6.1. 
Summary of safety data............................................................................................ 95 
6.6.2. 
Safety data conclusion .............................................................................................. 97 
6.6.3. 
Benefit/risk assessment ............................................................................................ 97 
7. 
TREATMENTS ..................................................................................................................... 99 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS .............................................................................. 99 
7.2. 
PACKAGING AND LABELING ................................................................................................ 99 
7.2.1. 
Packaging ............................................................................................................... 99 
7.2.2. 
Labeling .................................................................................................................. 99 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ....................................... 100 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................. 100 
7.5. 
STORAGE CONDITIONS .................................................................................................... 100 
7.6. 
DISPENSING OF TREATMENT ............................................................................................ 100 
7.7. 
TREATMENT REPLACEMENT .............................................................................................. 101 
7.8. 
PROCEDURE FOR BLINDING .............................................................................................. 101 
7.9. 
PROCEDURE FOR UNBLINDING ......................................................................................... 101 
7.10. STUDY DRUG COMPLIANCE ............................................................................................... 102 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................ 102 
7.12. OTHER MEDICATION ........................................................................................................ 102 
7.12.1. 
Handling of concomitant medication ........................................................................ 102 
7.12.2. 
Non-permitted medication (see Table I in APPENDIX III: Permitted/non-permitted 
medication) ........................................................................................................... 103 
7.12.3. 
Permitted medication under condition (see Table II in APPENDIX III: 
Permitted/non-permitted medication) ...................................................................... 103 
7.12.4. 
Permitted medication ............................................................................................. 104 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................. 105 
8.1. 
DEFINITIONS ................................................................................................................... 105 
8.1.1. 
Adverse events ...................................................................................................... 105 
8.1.2. 
Serious adverse events ........................................................................................... 106 
8.1.2.1. 
Life-threatening adverse events ................................................................................................ 106 
8.1.2.2. 
Inpatient or prolonged hospitalization ...................................................................................... 106 
8.1.2.3. 
Significant or incapacitating disability ....................................................................................... 107 
8.1.2.4. 
Medically important conditions .................................................................................................. 107 
8.1.3. 
Clarification on serious adverse events: .................................................................... 107 
8.1.4. 
Adverse drug reaction ............................................................................................ 108 
8.1.5. 
Unexpected adverse event ...................................................................................... 108 
8.2. 
ASSESSMENTS ................................................................................................................. 108 
8.2.1. 
Intensity assessment .............................................................................................. 108 


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8.2.2. 
Relation to the study treatment ............................................................................... 109 
8.2.3. 
Action taken and outcome ...................................................................................... 109 
8.3. 
REPORTING ..................................................................................................................... 110 
8.3.1. 
Reporting an adverse event .................................................................................... 110 
8.3.2. 
Reporting a serious adverse event ........................................................................... 110 
8.3.3. 
Follow-up .............................................................................................................. 112 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 112 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 112 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 112 
8.6.1. 
Pregnancy ............................................................................................................. 113 
8.6.2. 
Medication error..................................................................................................... 113 
8.6.3. 
Misuse .................................................................................................................. 113 
8.6.4. 
Overdose .............................................................................................................. 113 
8.6.5. 
Abuse ................................................................................................................... 114 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 115 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 115 
9.2. 
ENDPOINTS ..................................................................................................................... 115 
9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 115 
9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 115 
9.2.3. 
Key Secondary Endpoints ........................................................................................ 116 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 116 
9.2.5. 
Exploratory endpoints ............................................................................................. 118 
9.3. 
ANALYSIS SETS ................................................................................................................ 118 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 118 
9.4.1. 
Resolution of NASH ................................................................................................ 118 
9.4.2. 
Long-term endpoints .............................................................................................. 119 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 119 
9.5.1. 
Key secondary endpoint.......................................................................................... 119 
9.5.2. 
Other secondary endpoints ..................................................................................... 120 
9.5.3. 
Subgroup analyses ................................................................................................. 120 
9.5.4. 
Exploratory analyses .............................................................................................. 121 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 121 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 121 
9.7.1. 
Resolution of NASH ................................................................................................ 121 
9.7.2. 
Time to clinical event/death .................................................................................... 122 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 123 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 123 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 124 


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10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 125 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 125 
10.2. RETENTION OF RECORDS ................................................................................................. 125 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 127 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 127 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 128 
11.3. QUALITY ASSURANCE ....................................................................................................... 128 
12. 
ETHICS AND REGULATORY................................................................................................ 129 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 129 
12.2. COMPETENT AUTHORITY .................................................................................................. 130 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 130 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 130 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 131 
13. 
FINANCING AND INSURANCE ............................................................................................ 132 
13.1. FINANCIAL ISSUES ........................................................................................................... 132 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 132 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 133 
14.1. STUDY REPORT ................................................................................................................ 133 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 133 
15. 
REFERENCES LIST ............................................................................................................ 135 
APPENDICES .................................................................................................................................. 138 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 139 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 147 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 148 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 150 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 151 
 
 
 


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TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
31 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
35 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
96 
 


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TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
39 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
40 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
AFP 
Alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase 
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
DSMB 
drug-induced liver injury 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
full safety set 


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GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP-1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IQR 
InterQuartile Range 
IR 
Insulin Resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model End stage Liver Disease 
NAFL 
 
nonalcoholic fatty liver  
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
PBC 
National Cholesterol Education Program’s Adult Treatment Panel III  
Primary Biliary Cholangitis 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
Steatosis - activity - fibrosis 


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SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reaction 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
UDCA 
Tumor Necrosis Factor-alpha 
UrsoDeoxyCholic Acid 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD where 
steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) and 
the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue owing 
to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high prevalence 
of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in Europe and 
27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance spectroscopy, 
34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte FFA 
load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver (second 
hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor cells and 
associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse range and 
high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate cells (HSC) 


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and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic factors that 
recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to fibrogenesis. 
collagen and other extracellular matrix components accumulate within the liver, which may result in distortion 
of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can be considered as 
the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in disease 
progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing injurious 
and fibrotic mechanisms resulting in disease progression, it should not be considered a sole therapeutic 
target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the “second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been associated 
with a reduction in generation of reactive oxygen species and Kupffer cell activation, which might attenuate 
injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin contributes to an 
insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells are 
the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the proapoptotic 
gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, caspase levels, by-
products of cellular apoptosis, are also increased in these groups of patients. 


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1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the fibrate 
class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis and 
upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in serum 
triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in cholesterol 
efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and C-reactive 
protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with fibrates 
in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with clofibrate 
in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or triglycerides 
levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via improved 
insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory responses, 
and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the potential to 
target multiple components of the metabolic syndrome, including obesity, dyslipidemia, hypertriglyceridemia, 
insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice compared 
to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak inducer of 
apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ as 
a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory macrophages.17,18 These studies demonstrate that PPARδ encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin sensitivity, 
and suppresses inflammation. The finding raises the possibility that small molecule agonist of PPARδ may be 
effective therapeutic targets for the treatment of chronic inflammation in the liver. 


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The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, in 
several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with elafibranor 
confers liver protection both in preventive and therapeutic approaches on established pathologies. These 
effects have been demonstrated through plasma and hepatic markers, as well as liver macro- and micro- 
histological examination. These studies have shown that elafibranor acts on several mechanisms involved in 
NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have 
demonstrated that both PPARα-dependent and PPARα-independent mechanisms participate in the beneficial 
effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor has 
insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic treatment 
of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic plaques in 
the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was moderate 
(about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by the active 
metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both elafibranor and 
GFT1007 linearly increase with the dose after single or repeated administrations. Elafibranor and its 
metabolites are rapidly cleared from the plasma and they are totally excreted by both fecal and renal route 
within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into the bile and undergo 


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an extensive entero-hepatic cycle giving support for liver targeting of elafibranor and/or GFT1007. The 
distribution study in the rat supports the liver targeting of elafibranor and/or its metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. Thus, 
the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug metabolism 
should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed through a clinical 
study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of elafibranor 120 mg 
administered for 14 days alone or with a single administration of warfarin. This study demonstrated that 
elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal metabolite 
GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the potential for 
drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, elafibranor 
(GFT505) has recently been assessed in a follow-up clinical DDI study with the OATP1B3-sensitive substrate, 
atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no evidence 
of the formation of unique human metabolites or metabolites formed at disproportionately higher levels in 
human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 


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1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose oral 
administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year repeated-dose 
carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated hepatomegaly, 
hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). However, it is well known 
that, compared to nonhuman primates and humans, rodents are highly sensitive to PPARα agonist induced 
peroxisome proliferation and associated liver side effects. Thus, available information on this class of drug 
which includes marketed fibrates together with the lack of any liver side effects in monkeys treated with high 
doses of elafibranor for 1 year support the nonrelevance to human.19 Overall, these studies did not reveal 
any other safety issues up to the highest doses tested. Notably, elafibranor did not have any of the known 
PPARγ-related concerns such as excess in weight gain, hemodilution, edema, cardiomegaly, adiponectin 
induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and the 
UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect level 
(NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered that data 
are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor (GFT505), 
and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
NASH 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 completed clinical trials, and 5 still ongoing. A total of 561 healthy lean subjects, 60 
overweight or obese subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 20 
with hepatic impairment (Child-Pugh class A, B or C) have been randomized to date in the completed trials. 
Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 


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A Phase 2 program was initiated to assess the safety and efficacy profile of elafibranor in subjects with 
cardiometabolic disorders and NASH. To date, 5 Phase 2a studies have been completed, in which 297 
subjects were randomized: 37 with mixed hyperlipidemia (type IIb Frederickson); 94 with atherogenic 
dyslipidemia and abdominal obesity; 47 with impaired glucose tolerance and abdominal obesity; 97 with 
diabetes mellitus type II; and 22 with insulin resistance and abdominal obesity. A Phase 2b study has also 
been completed, in which 274 subjects with NASH were randomized. In the Phase 2 program, the elafibranor 
daily doses ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months.  
A Phase 2a randomized, open-label, sequential cohort study (GFT505E-218-1) will assess the PK and 
pharmacodynamic (PD) profile and the safety and tolerability of two dose levels of GFT505 (80 mg and 120 
mg) in children and adolescents, 8 to 17 years of age, with NASH. In this study, subjects will receive 80 or 
120 mg of GFT505 once daily for 12 weeks. The study consists of two paediatric patient cohorts with NASH 
which will be dosed sequentially. Cohort 1 will consist of +/- 12 subjects who are ≥12 to ≤17 years of age. 
Once 10 subjects in cohort 1 have been evaluated for PK and safety through Visit 4 (30 days) by an 
independent Data Safety Monitoring Board (DSMB), enrollment will be open to subjects ≥8 to ≤11 years of 
age. Cohort 2 will consist of +/- 8 subjects who are ≥8 to ≤11 years of age.  
At time of DSUR data lock point (31 July 2019), 1 subject (≥12 to ≤17 years of age) had been enrolled and 
exposed to at least one administration of GFT505. 
A Phase 2 study (GFT505-219-8) to evaluate the effect of a 6-week elafibranor (120 mg) treatment 
administered once daily on hepatic lipid composition in subjects with nonalcoholic fatty liver (NAFL) is 
currently ongoing. This study intends to achieve mechanistic information about the mode of action of 
elafibranor on the (lipid) metabolism in the human fatty liver. Subjects with NAFL will receive 120 mg of 
GFT505 or placebo once daily for 6 weeks in randomized order in a crossover design. Overall, 16 subjects 
with NAFL are intended to be included. 
For additional information see Investigator’s Brochure. 
1.5.2. 
Primary Biliary Cholangitis (PBC) 
Based on the mechanism of action of elafibranor, and on the relevant efficacy and safety data collected to 
date, specifically on decrease in ALP and inflammation markers, a Phase 2a study has been launched in PBC 
has been completed, under IND 132202, filed in September 2016. The aim of this study was to validate the 
efficacy of elafibranor on ALP decrease in this patient population, and to confirm its safety in a population 
with PBC. This study was designed to compare the effect of daily oral administration for 12 weeks of GFT505 
80 mg and 120 mg on changes in serum alkaline phosphatase (ALP) to that of placebo in subjects with PBC 
and inadequate response to ursodeoxycholic acid (UDCA). 
For additional information see Investigator’s Brochure. 
 


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1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers.  
Moreover at the last DSUR cut-off date (31 July 2019), 25 clinical studies with elafibranor have been 
conducted or are ongoing (in which a total of 3245 subjects have been randomized, including an estimated 
2206 subjects exposed to elafibranor. In general, the treatment was well tolerated. No interaction, 
medication errors, or abuse/misuse cases have been reported to this date. See Section 6.6 for further 
information. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrates that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can progress 
to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with mild to 
moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a reasonable 
timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the evaluation 
of long-term outcomes including progression to cirrhosis should ensure that an expected number of events, 
calculated based on progression rate for each fibrosis stage, are obtained. Based on the literature,21,22,23,24,25 
in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be estimated at 8% per year 
for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. Generally, 
liver decompensation events occur only when cirrhosis is present and the progression rate to the other events 
is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk of 
fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the Phase 
I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In this model, 
the studied response was the change at endpoint versus baseline in biochemical parameters known to be 
associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes (ALT, GGT, alkaline 
phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based on this modeling, the 
optimum dose was consistently assessed as a value of 118 mg. Therefore, given its good safety profile and 
evidence of efficacy, both supported by the dose-response modeling, 120 mg elafibranor appears to be the 
most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 i.e., 
reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with increased 
hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies are now 
available showing that patients with steatohepatitis but not those with steatosis only (i.e., nonNASH NAFLD) 
are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis for "resolution of 
NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced by the academic 
community and expressed in several scientific society endorsed position papers.29,30 Based on the recently 
published recommendations from this workshop,30 resolution of NASH with no worsening of fibrosis may be 
an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and fibrosis. Based 


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on recent data that have shown that fibrosis stage of 2 or more is related to liver-related mortality,22 the “no 
worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (post-approval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score ≥15, 
hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, variceal 
bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, hepatopulmonary 
syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy [provided that 
these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most accurate 
estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 2145.5 person-years 
of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an 
improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a population of patients with 
NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 0.14 stage/year in a population 
of patients with NASH. In another study of 108 patients, no significant difference in the proportion exhibiting 
fibrosis progression was found between those with NAFLD or NASH.31 In the whole cohort, the mean annual 
rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths between 
treatment and control groups can be considered as a potential clinically meaningful outcome measure for 
clinical trials. This long-term outcome including progression to cirrhosis is considered acceptable,30 and 
required in a post-approval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH without 
worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  


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1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the chronic 
toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of elafibranor does 
not reveal any major safety concern, based on the conclusion that elafibranor-induced liver toxicity in rodents 
is not relevant to non-primates (no evidence of liver toxicity in monkeys after 1 year but improvement of 
liver function markers) and humans (consistent improvement of liver function markers in all Phase II trials). 
These toxicology results and conclusions are on-line with the extensive literature on the liver effects of PPAR 
agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine ratio, 
cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, kidney 
injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived estimated 
glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each visit, as well 
as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and will be reviewed 
on an ongoing basis through regular safety reviews by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the DSMB. 
In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored throughout the 
study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan measurement 
and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is suspected, a 
confirmation by liver biopsy will be performed. 


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For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of portal 
hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 


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• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to SAF scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 


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o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP AND THE OVERALL POPULATION 
(WHATEVER THE FIBROSIS STAGE – F1, F2 OR F3) 
• 
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or F3), 
the same endpoints as for the primary and secondary objectives. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize at least 2022 F2/F3 patients to either active (1348 patients) or placebo (674 
patients) treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the F2/F3 
enrolled patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 
at least 2 of the following conditions: persistent elevated (absence of normal ALT within the past year, 
obesity defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education 
Program’s Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also 
be enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of at least 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 3 
factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 


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• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 96 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be redefined 
according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory part of the 
study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 2, and Figure 1. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an 
event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) 
3.6.1. 
Screening visits SV1 and SV2: 
The following screening procedures will be performed for all potential patients at SV1 conducted during the 
screening period and prior to Randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 
• 
Physical examination (described in Section 6.2.1). 


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• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.3). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 6 months prior to Screening) (described in Section 7.12 
and APPENDIX III: Permitted/non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an additional 
SV2 visit at least Week -4 prior to the planned Randomization V1 in order to obtain the results in time. 
The following biological assessments  
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 
months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart in 
order to have 2 consecutive values for DILI adjudication. 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 32, and 33 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 3 digits corresponding to the site number (this number will be predefined), 
 Last 3 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended 
Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an additional 
SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood samples 
for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver biopsy. 
Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results from 
the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/non-inclusion status by a phone call within 
1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon 
as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the 
Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to 3, 
ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant cardiometabolic 
comorbidities, which are associated with rapid progression of the disease (listed in Section 3.1), will also be 
enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under treatment 
in order to evaluate the effect of elafibranor on the liver histology. 
When at least the first 1023 randomized patients (F2-F3) complete Week 72 (or discontinue early from the 
study treatment), a surrogate endpoint analysis will be performed and potentially filed for initial market 
approval under Subpart H or conditional approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in the 
permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX II: 
Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and 
tobacco habits 




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At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint described 
in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of the study 
following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 1 week 
before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX II: 
Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and 
tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 6.2.5) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.6) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous 
visit (for WOCBP only, every visit from V1) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4) 
• 
FibroScan (described in Section 6.2.5) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and tested 
at a local laboratory prior to the liver biopsy. 
• 
Ultrasonography of bladder and urinary tract (at V8 then every year [V10, V12…]) (described in 
Section 6.2.5). 


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3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP compliance 
control. If any information during this phone contact requires a visit, the Investigator may decide to perform 
an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop treatment 
and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after the 
final administration of study drug. Patients who permanently discontinue study drug for any reason other 
than an event listed in the primary composite endpoint for long-term efficacy described in Section 1.9.2 will 
remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy outcomes 
and safety through phone call visits every 24 weeks as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the site 
and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT Visit 
see Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return (if 
required). The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX II: 
Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and 
tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.5) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2), 
• 
Urinary pregnancy test (for WOCBP only)  
• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 


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• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
the onset of: 
 
variceal bleed 


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 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
 ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided 
that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional testing 
is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to Randomization 
(V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for safety 
reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.11.3. 
Specific monitoring 
If the conditional approval for elafibranor is not obtained upon submission of interim analysis results, patients 
will be asked to come back for a specific monitoring visit every year over 4 years after the end of the long 
term treatment period. 
These specifics visits will include: dosage of alpha-fetoprotein (AFP) and osteocalcin, urine 
cytology, and ultrasonography of urinary tracts and bladder. 


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3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding capability. 
Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as described 
below: 
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization. 
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning with 
a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal ALT 
within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III definition), 
type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has 
already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or UDCA; a stable dose from at least 6 months prior to diagnostic liver biopsy is 
required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic 
drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., 
implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, 
sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide 
(GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months 
prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable dose 
in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
10. Patients following adequate life style recommendations 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the 
course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 
6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 


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7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or five 
half-lives, whichever is longer, prior to Screening. 
18. Patients for whom life styles recommendations have never been introduced. 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept constant 
for at least 2 months prior to Screening. 


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20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known cancers. 
23. 
Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
24. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
25. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
26. Positive anti-human immunodeficiency virus (HIV) antibody. 
27. AST and/or ALT >10 x upper limit of normal (ULN). 
28. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
29. INR >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with 
markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
33. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 2, Figure 1, and 
Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for each 
patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 7 days. 
• 
On each study visit day, study treatment will be taken under fasting conditions after the blood 
sampling (which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 
• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. Alcohol 
consumption of more than 20 g per day for women and 30 g per day for men is considered abusive 


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(see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams (0.6 ounces) 
of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 2 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1). 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be permanently 
discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the Medical 
Monitor informed. If the discontinuation of study drug is due to an AE, the event should be documented in 
the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 


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• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of background 
therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever is 
sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible with 
this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 


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period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and 
is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to contact 
patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the site. Vital 
status will be collected within legal and ethical boundaries for all patients randomized, including those who 
did not get study drug. Vital status will be searched in public sources during the study close-out period. If 
vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of patients, 
but intends only to exercise this right for valid scientific or administrative reasons. After such a decision, the 
Investigator must contact all participating patients within a reasonable period of time. As directed by the 
Sponsor, all trial materials must be collected and all eCRFs completed to the greatest extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. Prompt 
compliance with this requirement is essential so that the Sponsor may comply with its regulatory obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 


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the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, and 
the risks to the patient should not outweigh the potential benefits. This will be assessed by the investigator 
according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in liver 
disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe biopsy 
should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies to 
determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. Biopsy 
slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Liverpat, 28 rue de l’amiral Hamelin, 75 116 Paris– 
France) where they will be read and scored. Scores for total NAS, steatosis, ballooning, lobular inflammation, 
or portal inflammation, as well as fibrosis scores (both by NASH CRN scoring system, and NAFLD Ishak 
scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT - Loos, 
France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 24 hours 
after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, signed, 
and dated by the Investigator as soon as they are received. The Investigator should comment upon out of 
range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described Section 3.11. 
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the site 
within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3). 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, at 
each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time of 
the approximate 4 year biopsy). Alfa-fetoprotein and osteocalcin will be tested every year from V1 up to end 
of study (at V1, V5, V8, V10, V12...). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale for 
weight must be the same for a given patient throughout the visits. 
6.2.2. 
Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in cm 
during expiration. The measuring tape should be snug but not compressing the skin and held parallel to the 
floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the exception 
of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement in Humans 
and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated manometer 
should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the LTTP. 
Where possible, FibroScan must be done at the day of visit. Otherwise, it can be performed within 7 days 
around the visit date.  
Recommendations for ensuring a reliable examination are:  
• 
Patient must be fasting for at least 2 hours before the FibroScan examination 
• 
At least 10 consecutive and successful measurements shall be performed without changing probe 
position 
• 
InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, 
to consider a FibroScan measure as reliable. If not, it is recommended to perform a few additional 
individual measures, or to restart the entire FibroScan examination 
Bladder and urinary tract ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year from V1 up to end of study (at 
V1, V5, V8, Vn…). Where possible ultrasonographic exam must be done at the day of visit. Otherwise, it can 
be performed within 7 days around the visit date. 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, V3, 
V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP until, 
and including the EOT visit. 


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6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, and/or 
marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 3 to 7 
days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle tenderness 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be considered and 
the patient must be discontinued from study treatment immediately and followed up as described in 
Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, the 
CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned randomization 
visit (V1), or, using lab results from SV1 and V1 that are at least 8 weeks apart. 
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once a 
week) 


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o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5 (except in case of anticoagulant therapy): 
permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and 
Section 5.2.2). 
• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash: permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 
and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND eosinophilia (>5%) with total count > ULN: permanently discontinue 
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any visit 
post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from study 
drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently discontinue 
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5 (except in case of anticoagulant 
therapy): permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 
and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT Visit 
(see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND eosinophilia (>5%) with total count > ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 


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6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
A liver biopsy may be considered in order to confirm the diagnosis of cirrhosis if during a LTTP visit the 
FibroScan value is ≥ 14 kPa (with IQR/Median stiffness ratio < 30%*) associated with a platelet count 
<150 000/mm3 and at least 1 elevated serum marker of fibrosis indicative of cirrhosis (calculated NAFLD 
fibrosis >0.676 score or reported FIB-4 >2.67). 
*InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, to 
consider a FibroScan measure as reliable. If not, it is recommended to perform a few additional individual 
measures, or to restart the entire FibroScan examination.  
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, such 
as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for diagnosis of 
cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will discontinue 
the study drug and the study and will be followed up as described in Section 5.2.2 and Section 5.2.3. 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events. A detailed description of 
the interim analysis procedures and decision-making process will be provided in the DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 hepatologist, 
1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the participants in 
the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite efficacy 
long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major 
cardiovascular events as defined in the CEC charter. The CEC assessment and adjudication will occur in a 
blinded, consistent, and unbiased manner throughout the course of a study to determine whether the 
endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist, all of whom will be 
independent of the participants in the study. 


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6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 completed and 5 ongoing clinical trials. A total of 659 volunteers were randomized in 
these studies performed in Phase I centers, including 561 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 20 with hepatic impairment 
(Child-Pugh class A, B or C) have been randomized to date in the completed trials. Elafibranor daily doses 
ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients suffering 
from cardiometabolic disorders and NASH. To date, 5 Phase IIa studies have been completed in which 297 
patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and safety of 
elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. A Phase 2 study (GFT505B-
216-1) was also conducted in Primary Biliary Cholangitis (PBC) and included 45 patients with PBC and 
inadequate response to UDCA. This study evaluated the efficacy and safety of elafibranor at doses of 80 mg 
and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor daily doses ranged between 
30 mg and 120 mg, with a maximum treatment duration of 12 months. 
Of the 63 Treatment emergent SAEs that have been reported cumulatively in the completed clinical 
development program, 50 occurred with elafibranor and 13 with placebo. For all SAEs, the treatment code 
has been broken (end of study unblinding). 
Of the 50 SAEs that occurred with elafibranor, only 10 SAEs reported in 7 subjects were considered as having 
a reasonable possibility of relationship to elafibranor by the investigators (serious adverse reaction). They 
consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg. 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in 
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease). 
• 
Autoimmune hepatitis in a 56-year-old subject after 12 weeks of treatment of 120 mg elafibranor.  
The subject received her last dose of investigational product before the event.  


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For atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease, after later investigations, 
given the medical history of the patients or the time of occurrence of the event, relationship to elafibranor 
was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the main 
symptoms were fatigue / asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
System Organ Class 
Adverse Reaction 
Severity 
Number of cases 
(Frequency %) 
Gastrointestinal disorders 
Diarrhea 
Mild to moderate 17 (2.8%) 
Vomiting 
Mild to moderate 9 (1.5%) 
General disorders and administration site 
conditions 
Fatigue / Asthenia 
Mild to moderate 17 (2.8%) 
Investigations 
Hepatic enzymes increased 
(mainly transaminases) 
Mild to severe 
13 (2.1%) 
Blood creatine 
phosphokinase increased 
Mild to moderate 6 (1.0%) 
Musculoskeletal and connective tissue 
disorders 
Myalgia 
Mild to severe 
9 (1.5%) 
Metabolism and nutrition disorders 
Decreased appetite 
Mild to severe 
9 (1.5%) 
Nervous system disorders 
Dizziness 
Mild to moderate 6 (1.0%) 
Skin and subcutaneous tissue disorders 
Rash 
Mild to moderate 8 (1.3%) 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 7 (1.1%) 


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based on creatinine). Myalgia, decrease of appetite dizziness and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical trials, 
given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is monitored in 
clinical trials. For this reason, it is recommended that investigators review these lab results in the course of 
clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our phase 
IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should also be 
monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014)34. 
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with highly effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol.  
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders and asthenia / fatigue are 
considered common non-serious adverse reactions reasonably associated with elafibranor. Most of them are 
of mild to moderate intensity. Laboratory increases in serum creatinine or CPK should be monitored 
throughout clinical trials as this has been observed in Phase II trials to date, and is a known PPARα agonist 
effect. Elevation of AT will be monitored as well as DILI. In the absence of extensive human pregnancy data, 
highly effective contraception should be maintained for women of childbearing potential participating in 
clinical trials with elafibranor treatment, up to 1 month after end of study treatment. 
6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential of 
elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy of 
elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial was 
short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg daily, 


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improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg concomitantly 
improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, total and 
LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and glucose 
homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the objective 
to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Furthermore, the Phase IIa trial in PBC subjects who had an inadequate response to UDCA demonstrated 
similar improvement in GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP levels 
was observed, resulting in significant treatment effects versus placebo on the primary endpoint, whilst also 
meeting the composite endpoint used for drug registration (i.e. serum ALP <1.67 x ULN, an ALP decrease 
>15% and total bilirubin <ULN). 
Moreover, these studies have highlighted the good safety profile of elafibranor and no major safety concerns 
have been raised. 
Despite this favorable benefit-risk profile, an independent DSMB is to be established in order to review the 
safety of the treatment during the trial in an unblinded manner, to protect patient welfare and preserve study 
integrity. The safety assessments will be performed on a regular basis, every 6 months after Randomization 
of the first patient. The DSMB will consist of 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 
hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all independent of the participants in the 
study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil blisters. 
This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use only” 
or other similar/appropriate statements as well as the following instructions “Please return empty packaging 
and unused products to your doctor at your next visit.” Details of carton and wallet labels are detailed in 
APPENDIX V: Product carton and wallet labeling. 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before breakfast 
with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages (containing 
96 tablets to last approximately 3 months) allocated to the site. The pharmacy will acknowledge receipt of 
the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when applicable, 
results of any retesting performed), and if the patient fulfills all criteria to enter the treatment period, the 
Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described in 
Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the final database lock and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and ensure 
the study drug is at site for the visits occurring. The IXRS will continue to project study drug requirements 
per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication containing 
the adequate number of wallets to cover the drug administration for the period between visits. The time 
between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment Period and 
24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond to the 
number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be reported 
in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned to active 
treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial medication 
to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of the 
study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or unused) 
and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may destroy 
used and unused study drugs in accordance with the site SOP and always after the drug accountability has 
been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
• 
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling) 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
7.12. OTHER MEDICATION 
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II in 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 


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within 6 months prior to Screening) and information should be communicated to the Medical Monitor in order 
to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.12.2. 
Non-permitted 
medication 
(see 
Table 
I 
in 
APPENDIX 
III: 
Permitted/non-permitted medication) 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
• 
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 72 weeks 
of treatment (see APPENDIX III: Permitted/non-permitted medication): 
• 
GLP-1 agonist 
• 
SGLT2 inhibitors. 
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition (see Table II in APPENDIX III: 
Permitted/non-permitted medication) 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes are allowed after Randomization if judged necessary by the physician): 
• 
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept 
stable for at least 2 months prior to Screening. 
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
• 
Vitamin E >400 IU/day 
• 
PUFAs >2 g/day 
• 
UDCA 


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The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 
• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an “as-needed” 
basis. Patients should be discouraged from starting any new medication without consulting the Investigator 
unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical 
(investigational) product and which does not necessarily have to have a causal relationship with this 
treatment will be considered as an AE. The term AE is synonymous with the term “adverse experience” as 
used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the Screening 
Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. 
The questions concerning whether the condition existed before the start of the active phase of the study and 
whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, but 
the severity or frequency increases during the active phase. The active phase of the study begins at the time 
of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of seriousness 
(as defined above) and considered to be possibly related (according to the Investigator) to any study-specific 
procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
• 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in the 
hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will not 


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be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social reasons 
will not be considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the protocol. 
Day or night survey visits for biopsy or surgery required by the protocol are not considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the study 
center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement due 
to a pre-existing condition of osteoarthritis of the knee that has not worsened during the study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 


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• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as SAE. 
Hospitalization or prolonged hospitalization for a complication of such procedures should be reported 
as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator’s Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 


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8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related to 
study treatment. The Investigator will evaluate any changes in laboratory values, make a determination as 
to whether or not the change is clinically important, and whether or not the changes were related to study 
drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or clinically 
significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration and 
it cannot be explained by the patient's clinical state or the study procedures/conditions. The AE 
abates upon discontinuation of the study drug and reappears when the study drug is introduced 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not likely 
because of other plausible explanations 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because information 
is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
• 
Recovered/resolved 


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• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the Screening 
Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s medical record 
from the ICF signature until study end for each patient. Whenever possible, symptoms should be grouped 
as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal intensity, 
action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion as to whether 
there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and which 
is considered by him/her to be caused by the study drug within a reasonable possibility, should be reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.1 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that are 
not confirmed by adjudication will be reported as described with the start of the reporting time window being 
the time of negative adjudication decision. 
Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator becoming 
aware of the event). 


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ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE Form. 
The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment of the 
event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to allow a 
complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 24 hours 
of becoming aware of additional information such as diagnosis, outcome, causality assessment, results of 
specific investigations, and any new significant information that has not been previously reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, autopsy 
reports, and other documents should be sent when requested and applicable. All provided reports must be 
anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the concerned 
Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned according to the 
country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical research 
organization (CRO) may be required to expedite report to the Regulatory Authorities for: 
• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs). 


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Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information included 
in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the patient 
has left the study and that additional investigations may be requested by the Sponsor. This information 
should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and which 
is considered by him/her to be caused by the study drug within a reasonable possibility, should be reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 
8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or overdose, 
and reports associated with product complaints. 


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8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow reasonable 
attempts to be made to obtain information on any possible medicinal product exposure to an embryo or 
fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be reported 
as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as appropriate 
(see Section 8.3). 
8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or cumulatively, 
which is above the maximum recommended dose according to the authorized product information (see 
Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 


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8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP may 
be revised during the study only to accommodate protocol amendments and to make changes to adapt to 
unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis and 
stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 72 weeks 
of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) and 
disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall pattern of 
injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN fibrosis staging 
system and defined as progression of at least 1 stage. This surrogate endpoint will be formally assessed at 
the time of the surrogate efficacy analysis when at least first 1023 randomized  F2 and F3 patients complete 
the 72 week treatment period or discontinue early from the study treatment (see Section 9.8.1 for details). 
An additional exploratory analysis of this endpoint will take place at the time of the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 


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• 
HCC 
• 
the onset of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 96 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoints 
The key secondary endpoints are: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL 
cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
These key secondary endpoints will be assessed at the time of the surrogate endpoint analysis (at least the 
first 1023 randomized patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening 
of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring without worsening of NASH 


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o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores (NASH CRN 
scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 1 point 
improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activity-
fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 
point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score according 
to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 


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o 
liver-related death events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main analysis 
of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all F2 and F3 patients who receive at least 1 dose of study drug. This set will be 
used to summarize safety. 
• 
Efficacy evaluable set (EES): All F2 and F3 patients in the ITT population who have taken at least 
one dose of study treatment and have a reliable liver biopsy at both baseline and at the end of the 
72 week treatment period. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all r patients who receive at least 1 dose of study drug. 
Patients in the ITT, FITT, EES, PPS, and exploratory F1 cohorts (study population and efficacy data) will be 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 


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The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. According to the method described in Ge et al. (2011)36, 
the statistical model will be used to estimate the difference (elafibranor/placebo) in rate of resolution of 
NASH without worsening of fibrosis and its 99% CI. The main confirmatory analysis will be performed when 
at least the first 1023 randomized F2/F3 patients have completed the 72 week treatment period or 
discontinued early from the study treatment. The main analysis will be based on the ITT. Supportive analysis 
will be based on the EES and PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Supplementary analyses using multiple imputations and a pattern 
mixture model will be performed, as well as sensitivity analysis using a Cochran-Mantel-Haenszel test. Further 
details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. The time to clinical event/death will also be analyzed 
using an unadjusted Cox-proportional hazard’s model, log rank test and a nonparametric randomization 
based analysis of covariance method proposed by Saville and Koch.37  
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at the 
end of the 72 week treatment period will be summarized separately by treatment group. The data will be 


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analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, fibrosis 
stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the surrogate 
endpoint analysis when at least the first 1023 randomized patients with fibrosis stage F2 and F3 have 
completed the 72 week treatment period or discontinued early from the study treatment. The null hypothesis 
will be tested at the two-sided 0.01 alpha level. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant. A gatekeeping procedure will be constructed to control the overall Type I error rate for testing 
the key secondary efficacy endpoints at an overall two-sided alpha level of 0.01.  
The main analysis will be based on the IIT. Supportive analyses will be based on the EES and PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution of 
NASH without worsening of fibrosis. 
Time to event endpoints such as time to first cardiovascular event/death will be analyzed using the Cox 
proportional hazard’s model in the same manner as time to clinical event/death. 
Continuous endpoints will be analyzed using a repeated measures Analysis of Covariance (ANCOVA) model 
with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage, baseline NAS, and time-point and 
treatment by time-point interaction. A compound symmetry covariance matrix will be used for this analysis. 
The statistical model will be used to calculate the mean treatment difference and 95% confidence interval. 
If the data does not meet the required assumptions for parametric tests, the data will be analyzed using a 
nonparametric analysis of covariance method of Zink and Koch.41  
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 


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• 
Age (<60, ≥60 years). 
• 
PNPLA3 (absence or presence of risk allele G [i.e. CC vs GG/CG], and within the at risk group, 
homozygous vs. heterozygous for the risk allel G [i.e. CG vs GG]) 
• 
Patients under statins (yes/no), defined as patients who have duration of IP exposure greater or 
equal to 60 days, with extent of exposure to statin greater than or equal to 30 days before the visit 
7 biopsy date.  
Forest plots will be generated for each of these endpoints for patients in the ITT population.  
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort and the 
FITT. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the primary 
endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided α=0.04 for 
time to clinical event/death. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant at a two-sided 1% significance level. A gatekeeping procedure will be constructed to control the 
overall Type I error rate for testing the key secondary efficacy endpoints at an overall two-sided alpha level 
of 0.01. 
The gatekeeping procedure will be detailed in the SAP and set up using the general method for building 
multi-stage parallel gatekeeping procedures in multiplicity problems with several families of null hypotheses 
(Dmitrienko and Tamhane, 2011, 2013).38,39 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected subgroups. 
In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 


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• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate based 
on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for patients 
with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of at least 1023 patients provides 90% power to show that 
elafibranor is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was estimated 
to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a conservative approach, 
no additional event rate was added for other events than histological cirrhosis or cirrhosis decompensation 
events. An annual clinical event/death rate of 7% was thus defined for the composite of both these 
endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver fibrosis. 
In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an approximate 
annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 80% power to 


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show that elafibranor is superior to placebo with respect to time to clinical event/death. In order to obtain 
456 events, at least 2022 patients will be required in the IIT. 
The number of patients to be enrolled may be adjusted during the course of the study in a blinded manner 
to achieve the desired number of primary events.  This will be accomplished using standard event forecasting 
methods (Anisimov, 2011).40 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be summarized 
by worst severity and relationship to study drug. Serious AEs, and AEs leading to discontinuation will also be 
summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change from 
baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values for 
each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. 
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when at least the first 1023 
randomized F2 and F3 patients complete 72 weeks of treatment or discontinue early from the study 
treatment. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. A Data integrity 
plan will be set-up to detail the blinding/unblinding process and address how data will be published in view 
of marketing authorization and how integrity of the trial will be protected. 


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The DSMB will periodically review safety data from the study to ensure the well-being of study participants. 
One dedicated meeting will also be held upon availability of the surrogate endpoint analysis results.  
DSMB will be provided with data summaries that will include selected efficacy results so that the DSMB can 
assess the likely benefit-risk profile of elafibranor. These are not considered a formal interim analysis, and 
no type I error adjustments will be done for these reviews. Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 456 
required events) have been accrued. The interim analysis will be performed by an unblinded team separate 
from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis results and 
provide final recommendations regarding trial termination due to futility and adjustment of the target number 
of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed specifically 
for this study. The CRF being used for this study is an electronic CRF that has been fully certified as being 
compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data 
capture). Patients will not be identified by name in the eCRF or on any study documents to be collected by 
the Sponsor (or designee), but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in the 
eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized person 
and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. However these documents should be retained for a longer period if required by 
the applicable regulatory requirements or by an agreement with the Sponsor. All hospital records will be 
archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, another 
institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for clinical 
investigators, the eCRFs and instructions for their completion and return, the procedure for obtaining 
informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In addition, the Study 
Monitor will explain the Investigator’s reporting responsibilities and all applicable regulations concerning the 
clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the Sponsor 
deems is necessary to determine that data recording and protocol adherence are satisfactory. A Study 
Monitor from 
 Late Stage Development Services will be responsible for monitoring this clinical trial. 
To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent contact through 
verbal and written communication. The eCRFs and related source documents, as well as drug accountability 
will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs and Good Clinical 
Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a requirement for 
participation in this study and any other medical records required to confirm information contained in the 
eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical data 
and source document review of critical processes, and will be supported by formal remote site monitoring 
activities. Centralized monitoring activities will review study data to assess changes in individual site risk and 
to identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer questions, 
and to provide any missing information. 


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All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and 
all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the Sponsor 
and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help identify 
missing data, selected protocol violations, out of range data, and other data inconsistencies. Requests for 
data clarification or correction will be electronically provided to the investigative site for resolution. Clinical 
data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be obtained 
from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in research studies. 
Prior to the study onset, the protocol, ICF, advertisements to be used for patient recruitment, and any other 
written information regarding this study to be provided to the patient or the patient’s legally acceptable 
representative must be approved by the IRB/IEC. The Sponsor will supply relevant material for the 
Investigator to submit to the IRB/IEC for the protocol’s review and approval. Verification of the IRB’s 
unconditional approval of the protocol and the written ICF statement will be transmitted to the Investigator. 
Documentation of the relevant IRB/IEC approval and of the IRB/IEC compliance with GCP guideline will be 
maintained by the site and will be available for review by the Sponsor or its designee or by the authorized 
members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a formal 
protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent protocol 
amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to the 
Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing direct 
access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 1 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, Amendments 
will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific procedures 
are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent must be 
reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC). 
The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In accordance 
with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF approved by 
the designated IRB/IEC and will be signed and personally dated by the patient or by the patient’s legally 
acceptable representative and by the person who conducted the informed consent discussion prior to 
protocol-specific procedures being performed. A separate consent form will be obtained for optional genetic 
and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by protocol 
number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall not 
be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable and 
necessary medical treatment for the injury, to the extent the expenses are not covered by the patient’s 
medical insurance, a government program, or other responsible third party. If laws or regulations of the 
locality in which the trial is taking place require additional payment of expenses, the Sponsor shall comply 
with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or paraclinical 
examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to ICH 
E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 Guideline 
for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality Assurance audit, 
the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators (or 
any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any third 
party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation of 
confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such results, 
which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the screening 
of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their studies, 
using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the manuscript 
or abstract for review by the Sponsor, and, if necessary, delay publication or communication for a limited 
time in order to protect the confidentiality or proprietary nature of any information contained therein. The 
Sponsor may also request that the Sponsor’s name and/or names of one or several of its employees appear 
or not appear in such publication. 
 
 


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21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic 
fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy 
studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy testing in clinical trials. Available at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-adjusted difference 
in proportions from clinical trials using logistic regression and weighted risk differences. Drug 
Information Journal, 45(4), 481-493. 
37. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
Trials Using Cox Proportional Hazards Models and Nonparametric Randomization Based Analysis 
of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
38. Dmitrienko, A., Tamhane, A.C. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011 30: 1473-1488. 
39. Dmitrienko, A., Tamhane, A.C.  General theory of mixture procedures for gatekeeping. 
Biometrical Journal. 2013 55: 402-419. 
40. Anisimov, V. Predictive event modelling in multicentre clinical trials with waiting time to response. 
Pharmaceutical Statistics. 2011; 10, 517-522. 
41. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 
 
.  
 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1.
e.g., gin, rum, vodka, whiskey.
2.
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm).


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration instructions 
X 
X 
“For Clinical Trial Use only.” 
X 
X 
“Keep out of reach of Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product and package return at next visit 
X 
X 


















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SUMMARY OF CHANGES 
AMENDMENT 4: 2020 
Amendment 4 is a substantial change to address the change in definition of the primary clinical benefit endpoint and associated adjudication process.  In addition, updates 
have been made to clarify the criteria to be used to identify patients with potential DILIs. A list of adverse events of special interest has also been added and clarification 
made on the required follow-up of the potential treatment related to adverse events. An additional section has been added to address the optional solutions put in place in 
case a patient participating in the GFT505-315-1 study cannot attend a site visit during the COVID-19 crisis or future crisis situation. 
 
Added text is bolded; deleted text is struck through. 
 
 
Summary of major changes to the protocol: 
Section 
New Text 
Section 1.9.2 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal hypertension/cirrhosis 
related events (liver transplantation, model end stage liver disease (MELD) score ≥15, hepatocellular carcinoma (HCC), and 
hospitalization due to occurrence of hepatic encephalopathy, or variceal bleeding, spontaneous bacterial peritonitis, and 
uncontrolled ascites requiring treatment), hepatorenal syndrome, hepatopulmonary syndrome, and chronic 
gastrointestinal blood loss due to portal hypertensive gastropathy [provided that these lead to hospitalization or 
transfusion]). 
Section 2.1.2 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a composite endpoint 
composed of death due to any cause, histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related 
events: 
• 
Liver transplantation 
• 
MELD score ≥15 for patients with baseline MELD score ≤12 
• 
HCC 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring hospitalization, 


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Section 
New Text 
o
spontaneous bacterial peritonitis,
o
ascites requiring treatment.
o
hepatorenal syndrome
o
hepatopulmonary syndrome
o
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to
hospitalization or transfusion).
Section 2.6 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
•
SAE, AE, AESI, physical examination, vital signs, medical history, ECG
•
hematological parameters
•
liver markers
•
renal biomarkers (including urinalysis)
•
cardiac biomarkers
•
metabolic parameters
•
other biochemical safety markers.
Section 3.10 
Patients who have permanently discontinued study drug due to an event listed in the primary composite endpoint for 
long-term efficacy described in Section 1.9.2 will be discontinued from the study following the EOT Visit and have no 
further follow-up, unless the patient experiences at the time of EOT visit, an ongoing adverse event possibly 
related to study treatment for which the follow-up should last until resolution of this adverse event. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, in the study 
and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following the EOT Visit to report 
safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) including liver and cardiovascular 
events until EOS or the occurrence of an event listed in the primary composite endpoint for long-term efficacy 
(described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have permanently 


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Section 
New Text 
discontinued study drug: 
•
IXRS registration.
•
Reporting of safety information regarding:
o
any new AEs
o
resolution of previous AEs
o
change in severity of existing AEs
o
occurrence of any cardiovascular events
o
occurrence of diabetes (for patients not previously diagnosed with diabetes)
o
worsening of diabetes (for patients previously diagnosed with diabetes).
•
Reporting of any change in diet and life style factors
•
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation
•
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation of cirrhosis)
•
Reporting of any of the following events (primary composite endpoint for long-term efficacy evaluation):
o
liver transplantation
o
MELD score ≥15 for patients with baseline MELD score ≤12
o
HCC
o
the onset of:

variceal bleed requiring hospitalization

hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring
hospitalization

spontaneous bacterial peritonitis

ascites requiring treatment.

hepatorenal syndrome

hepatopulmonary syndrome

chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these
lead to hospitalization or transfusion).

Death due to any cause
Section 3.12  
(changes from 
protocol version 
4.1) 
3.12 OFF-SITE STUDY PROCEDURES IN CASE OF CRISIS SITUATION 
Based on assessment of risk, and to ensure patient safety and minimize risks to trial integrity, the sponsor determined that 
the following optional off-site study procedures can be performed in case a study participant cannot attend an on-site visit 


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Section 
New Text 
during the COVID-19 crisis: 
•
Safety assessment via phone call
•
Local lab assessment
•
Delivery of the study treatment to patient
•
Visit to patient’s home
These options apply to all on-site study visits except for the randomization visit (Visit 1).  Visit 1 must occur on-site as per 
section 3.7.1.   
These solutions can be applied depending on the investigator’s judgment of each case and the patient’s agreement. The 
alternative solutions can be implemented in response to the COVID-19 crisis prior to the notification or submission to and 
approval of regulatory agencies and ethics committees. 
Before implementing any of these options for a patient, the site will contact the patient to check whether he/she agrees 
with the off-site procedures. 
The patient will be invited to attend an on-site visit to complete the study procedures as per protocol, as soon as the 
situation allows it. 
In cases of any future emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure patient safety 
and minimize risks to trial integrity, after completion of a risk assessment similar measures could be taken. 
3.12.1 Safety and drug compliance procedures 
The following procedures will be performed via either a phone contact, or, if safe and possible, a direct visit to the patient: 
•
Check for AEs and occurrence of any clinical outcome (described in Section 6 and Section 8)
•
Report any change in diet and lifestyle factors
•
Check concomitant/prior medication (described in Section 7.12 and
APPENDIX III: Permitted/non-permitted medication)
•
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since previous visit
(for WOCBP only, every visit from V1)
•
Drug accountability
o
dates of any study drug interruption since the last dispensation and reason*
o
end of treatment (if applicable): date of last dose of study drug and reason*


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Section 
New Text 
o
end of study (if applicable): date of end of study and reason*
*if the reason is related to an AE, collect all required details
•
Physical examination if possible with a direct visit to the patient (described in Section 6.2.1)
•
Record vital signs and weight if possible with a direct visit to the patient (described in Section 6.2.1 and
Section 6.2.3)
•
Based on the study visit period for the patient, excluding the quality of life assessment, additional protocol related
procedures of Section 3.7.2 or Section 3.8.1 may be performed if possible and if necessary conditions are met
3.12.2 Local lab assessment 
The patient will be asked if he/she can access a local lab in the few days after the phone contact to obtain 
hematology, biochemistry and urinalysis testing.  
If a direct visit to the patient is safe and possible, the appropriate lab parameters corresponding to the on-site 
study visit as described in Table 2 will be collected. 
3.12.3 Delivery of study treatment to the patient 
The IXRS registration will be completed to trigger study drug kit assignments, and the assigned drug kits can be 
shipped to the patient, or delivered directly to the patient by the site study staff if safe and possible. 
As per the usual study visit, the patient will be instructed to continue taking the available tablets from the existing 
kit until he/she receives the new kit. 
The study drug compliance and study drug accountability will be performed as described in Section 7.10 and 
Section 7.11 once brought to the study site/study pharmacy. 
3.12.4 Completion of Missed Study Procedures 
As soon as the situation allows it, the site will schedule the patient’s on-site visit to complete the missed study 
procedures (those that could not be performed during the phone calls/visit to patient) as per protocol (see 
Section 3.7.2 or Section 3.8.1). 
Section 5.2.2 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for long-term 
efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with no further follow-up after 
the EOT Visit, unless the patient experiences at the time of EOT visit, an ongoing adverse event possibly 


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Section 
New Text 
related to study treatment for which the follow-up should last until resolution of this adverse event. 
Section 5.2.3 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or possibly related 
AEs until the unresolved SAEs or possibly related AEs are judged by the Investigator to have stabilized. 
Section 6.3.2 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be adjudicated by the 
Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see  Section 6.5). 
Criteria used for reporting a potential DILI for adjudication are given below and correspond to the criteria 
leading to permanent study drug discontinuation. 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total bilirubin, and INR 
results meeting the requirements of within 8 weeks to 6 months of planned randomization visit (V1), or, using lab results 
from SV1 and V1 that are at least 8 weeks apart. 
Section 6.5 
The CEC will conduct adjudication of all disease progression events included in the primary composite efficacy long-term 
endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and all major cardiovascular events as defined 
in the CEC charter. The CEC assessment and adjudication will occur in a blinded, consistent, and unbiased manner 
throughout the course of a study to determine whether the endpoints meet the protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, and 1 endocrinologist and 3 histopathologists, all of 
whom will be independent of the participants in the study. 
Section 7.12.2 
Sentence “(see Table I in APPENDIX III: Permitted/non-permitted medication)” removed from the title 
Section 7.12.3 
Sentence “(see Table II in APPENDIX III: Permitted/non-permitted medication)” removed from the title 
Section 8.1.2 
8.1.2 Adverse event of special interest (AESIs) 
AESIs are treatment emergent AEs corresponding to the conceptual definition of: 
•
CPK elevations of severe intensity or leading to permanent study drug discontinuation


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Section 
New Text 
•
Muscle injury symptoms of severe intensity corresponding to:
o
Muscle pain or Myalgia
o
Muscle spasms or Tremor
o
Muscle weakness
•
Transaminases elevations from baseline of severe intensity or leading to permanent study drug discontinuation
•
Liver injury events of severe intensity corresponding to:
o
Hepatic impairment
o
Hepatic failure
•
Gastrointestinal symptoms of severe intensity corresponding to:
o
Abdominal pain
o
Constipation
o
Diarrhea
o
Nausea
o
Vomiting
o
Acute cholecystis
o
Acute pancreatitis
•
Fatigue and Asthenia of severe intensity
•
Serum creatinine elevations of severe intensity or leading to permanent study drug discontinuation
•
Renal injury events of moderate or severe intensity corresponding to:
o
Renal failure
o
Renal impairment
o
Renal colic
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are described in the 
section 8.6.1. 
Section 8.3.2 
8.3.2 Reporting a serious adverse event or an adverse event of special interest 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
AESI reporting starts from first study drug intake and ends at study end for each patient. 
Any SAE or AESI that is brought to the attention of the Investigator at any time after the reporting period and which is 
considered by him/her to be caused by the study drug within a reasonable possibility, should be reported. 






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Section 
New Text 
EoT visit), notably for the potential related adverse events, and that additional investigations may be requested by 
the Sponsor. This information should be documented in the patient’s medical records. 
Section 8.5 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities that are 
considered clinically relevant by the Investigator must be recorded as an AE, AESI or SAE as applicable. 
Section 8.6.1 
The pregnancy itself is not considered an AE. 
Section 9.2.2 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, histological 
liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
•
Liver transplantation
•
MELD score ≥15 for patients with baseline MELD score ≤12
•
HCC
•
the onset of:
o
variceal bleed requiring hospitalization,
o
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring hospitalization,
o
spontaneous bacterial peritonitis,
o
ascites requiring treatment,
o
hepatorenal syndrome
o
hepatopulmonary syndrome
o
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that these lead to
hospitalization or transfusion).
Section 9.8 
Safety data (exposure, AEs, AESI, clinical laboratory tests, vital signs, and ECGs) will be summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety analysis will 
be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). An 
overall summary of AEs will be provided. The number and percentage of patients reporting AEs will also be presented by 
MedDRA System Organ Class and preferred term. The AEs will be summarized by worst severity and relationship to study 


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Section 
New Text 
drug. AESIs, serious AEs, and AEs leading to discontinuation will also be summarized. Narratives will be added for all SAEs 
and AESIs. 
Section 10.1 
All study required patient data generated during the study will be recorded in the eCRF, with the exception of SAE/AESI 
forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic data capture). 
Section 11.1 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for clinical investigators, 
the eCRFs and instructions for their completion and return, the procedure for obtaining informed consent, and the 
procedure for reporting AEs and SAEs/AESIs with the Investigator. 
Section 12.5 
End of the research corresponds to the end of participation (end of study EOT Visit) of last observation for the last 
patient participating in the research. 


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Summary of minor changes to the protocol: 
The following minor changes were made to the protocol. The changes do not impact the reliability of the 
data generated in the clinical trial or the safety or rights of the subjects: 
AESI has been added to the List of Abbreviations. 
 The version number and date were updated throughout the protocol. Relevant sections of the synopsis 
were updated to keep consistency with the protocolStudy contact details for central laboratory have been 
updated. 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy 
analysis, followed by a Long-term Treatment Period (LTTP) to assess efficacy on progression to cirrhosis, 
all-cause mortality, and liver-related clinical outcomes as measured by the onset of any of the listed 
adjudicated events. 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD]) 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
Primary objectives – surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
•
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for
steatohepatitis.
•
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging
system and defined as progression of at least 1 stage.
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of 
portal hypertension/cirrhosis related events: 
•
Liver transplantation
•
MELD score ≥15 for patients with a baseline MELD score ≤12
•
the onset of:
o
variceal bleed requiring hospitalization,
o
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring
hospitalization,
o
spontaneous bacterial peritonitis,
o
ascites requiring treatment,
o
,
Key secondary objectives (at surrogate endpoint analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint: 


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•
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN
scoring.
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
•
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol,
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients)
Other secondary objectives: 
•
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the
following endpoints:
o
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of
LTTP)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to
NASH CRN scoring (at the end of LTTP)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to
NASH CRN scoring without worsening of NASH
o
percentage of patients with no worsening of Fibrosis and no worsening of NASH
o
percentage of patients with resolution of NASH and improvement of Fibrosis
o
percentage of patients with at least a 1 point improvement in histological scores
(NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation],
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system),
or portal inflammation
o
percentage of patients with improvement of NAS of at least 2 points
o
percentage of patients with improvement of NAS of at least 2 points and with at least
1 point improvement in hepatic ballooning
o
percentage of patients with at least a 1 point improvement in disease activity score (sum of
ballooning and lobular inflammation scores) according to NAS scoring and
steatosis-activity-fibrosis (SAF) scoring
o
percentage of patients with at least a 1 point improvement in disease activity score (sum of
ballooning and lobular inflammation scores) according to NAS scoring and with at least
1 point improvement in hepatic ballooning
o
percentage of patients with at least a 1 point improvement in disease activity score (sum of
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF)
scoring and with at least 1 point improvement in hepatic ballooning
o
percentage of patients with at least 2 points improvement in disease activity score
according to NAS scoring and SAF scoring
o
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis,
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score
o
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry
•
To assess the following endpoints at Week 72, and at the end of the LTTP:
o
changes in liver enzymes and liver markers
o
changes in noninvasive markers of fibrosis and steatosis
o
changes in lipid parameters
o
variation in body weight
o
changes in insulin resistance and glucose homeostasis markers
o
changes in inflammatory markers
o
changes in cardiovascular risk profile as assessed by Framingham scores
o
changes in liver stiffness by Fibroscan measurement
o
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire)
•
To assess the onset to:
o
histological liver cirrhosis
o
death of any cause
o
any portal hypertension or cirrhosis related events
o
cardiovascular events
o
liver-related death events.
Exploratory objectives 


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•
To constitute a biobank for discovery and validation of biomarkers in NASH.
Exploratory objectives for F1 group and the overall population (whatever the fibrosis stage – F1, F2 or F3) 
•
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or F3),
the same endpoints as for the primary and secondary objectives
Safety secondary objectives 
•
To assess the tolerability and safety of once a day administration of oral doses of elafibranor
120 mg:
o
serious adverse events, adverse events, adverse events of special interest, physical
examination, vital signs, medical history, electrocardiogram
o
hematological parameters
o
liver markers
o
renal biomarkers (including urinalysis)
o
cardiac biomarkers
o
metabolic parameters
o
other biochemical safety markers.
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Screening (if no 
historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
•
At least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration
scored 0-2, and lobular inflammation scored 0-3).
•
NAS ≥4.
•
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated alanine
aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by a
body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or
homeostasis model assessment of insulin resistance (HOMA-IR) >6.
At the end of the 72-week treatment period, patients will continue in the double-blind LTTP. Patients will be 
monitored by notably measuring the potential appearance of cirrhosis (based on FibroScan measurement 
for presence of cirrhosis associated with biological and clinical assessments). If histological cirrhosis is 
confirmed as well as any other event listed in the long-term composite endpoint, patients will be 
discontinued from study. 
Number of estimated randomized F2-F3 Patients: at least 2022 patients (ratio 2:1) 
•
674 patients in placebo group
•
1348 patients in elafibranor (GFT505) group
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~270 centers 
Number of participating countries: ~24 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech Republic, Russia, Turkey, USA, Canada, 
Mexico, Colombia,  Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 96 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
•
Screening Period: Week-12 to Week -1 prior to Randomization.
•
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or
placebo for 72 weeks.
•
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor
(GFT505) or placebo (until occurrence of prespecified number of events).
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1.
Males or females aged from 18 to 75 years inclusive at first Screening Visit.


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2.
Must provide signed written informed consent and agree to comply with the study protocol.
3.
Females participating in this study must be of non-childbearing potential or using highly efficient
contraception for the full duration of the study and for 1 month after the end of treatment, as
described below:
o
Cessation of menses for at least 12 months due to ovarian failure,
o
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented
ovarian failure
o
If requested by local IRB regulations and/or National laws, sexual abstinence may be
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of the patient)
o
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion,
vasectomized partner, or intra-uterine device)
o
Double contraception with barrier AND highly effective hormonal method of contraception
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal
contraception associated with inhibition of ovulation; oral, injectable, or implantable
progestogen-only hormonal contraception associated with inhibition of ovulation; or
intrauterine hormone-releasing system). The hormonal contraception must be started at
least 1 month prior to Randomization.
4.
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the
slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at
least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2,
and lobular inflammation scored 0-3).
5.
NAS ≥4.
6.
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of
normal value of ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome
(NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6.
7.
Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
o
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy
within 6 months before Screening is available)
o
1 liver biopsy after 72 weeks of treatment for assessment of the treatment effects on NASH
o
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has
already been performed within the past year
o
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological
confirmation).
8.
If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty
acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic
liver biopsy is required.
9.
For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:
o
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization
(i.e., implementation of a new anti-diabetic therapy) for patients treated with metformin,
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on
stable dose in the 6 months prior to diagnostic liver biopsy.
o
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment
(V7).
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating 
physicians’ judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver 
biopsy until the end of treatment. 
10. Patients following adequate life style recommendations.
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1.
Known chronic heart failure (Grade I to IV of New York Heart Association classification).
2.
History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in
the course of the study.


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3.
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.
4.
Type 1 diabetes patients.
5.
Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c
measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal
HbA1c (HbA1c >9.0%) leads to exclusion.
6.
Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was
discontinued at least 6 months before the diagnostic liver biopsy.
7.
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial
infarction, revascularization procedures).
8.
Weight loss of more than 5% within 6 months prior to Randomization.
9.
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis).
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system
are excluded.
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically
defined as higher than 20 g pure alcohol per day.
11. Pregnant or lactating females or females planning to become pregnant during the study period.
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures
including, but not restricted to:
o
positive hepatitis B surface antigen
o
positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or
positive HCV Ab at Screening)
o
suspicion of drug-induced liver disease
o
alcoholic liver disease
o
autoimmune hepatitis
o
Wilson’s disease
o
primary biliary cirrhosis, primary sclerosing cholangitis
o
genetic homozygous hemochromatosis
o
known or suspected hepatocellular carcinoma (HCC)
o
history or planned liver transplant, or current MELD score >12
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with
the recommendations of National Law in force applicable to clinical trials.
14. Patients who cannot be contacted in case of emergency.
15. Known hypersensitivity to the investigation product or any of its formulation excipients.
16. Patients with previous exposure to elafibranor.
17. Patients who are currently participating in, plan to participate in, or have participated in an
investigational drug trial or medical device trial containing active substance within 30 days or
five half-lives, whichever is longer, prior to Screening.
18. Patients for whom life styles recommendations have never been introduced.
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins,
ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage
has been kept constant for at least 2 months prior to Screening.
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to:
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to
Screening and up to end of treatment.
21. Currently taking any medication that could interfere with study medication absorption, distribution,
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g.,
indomethacin, which are not permitted from Randomization until end of treatment.
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known
cancers.
23. Patients with any history of cancer are excluded except patients with basal cell carcinoma.
24. Evidence of any other unstable or untreated clinically significant immunological, endocrine,
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease.
25. Mental instability or incompetence, such that the validity of informed consent or ability to be


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compliant with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
26. Positive anti-human immunodeficiency virus antibody.
27. Aspartate aminotransferase (AST) and/or ALT >10 x upper limit of normal (ULN).
28. Conjugated bilirubin > 1.50mg/dL due to altered hepatic function Note: Gilbert Disease patients
are allowed into the study.
29. International normalized ratio >1.40 due to altered hepatic function.
30. Platelet count <100,000/mm3 due to portal hypertension.
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females.
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than
60 ml/min/1.73 m2).
33. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated
CPK >3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest
should be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion.
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at surrogate endpoint analysis) 
To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH without worsening 
of fibrosis after 72 weeks of treatment. 
Long-term endpoint – clinical outcomes (at final analysis) 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of 
portal hypertension/cirrhosis related events: 
•
liver transplantation
•
MELD score ≥15 for patients with baseline MELD score ≤12
•
the onset of:
o
variceal bleed requiring hospitalization,
o
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring
hospitalization,
o
spontaneous bacterial peritonitis,
o
ascites requiring treatment.
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 96 months after the first patient is randomized. 
Key secondary endpoints (at surrogate endpoint analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
Other secondary endpoints 
•
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the
following endpoints:
o
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of
LTTP)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to
NASH CRN scoring (at the end of LTTP)
o
percentage of patients with improvement of fibrosis of at least 1 stage according to
NASH CRN scoring without worsening of NASH
o
percentage of patients with no worsening of fibrosis and no worsening of NASH
o
percentage of patients with resolution of NASH and improvement of Fibrosis
o
percentage of patients with at least a 1 point improvement in histological scores
(NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation],
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system),
or portal inflammation
o
percentage of patients with improvement of NAS of at least 2 points


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o 
percentage of patients with improvement of NAS of at least 2 points and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning 
and 
lobular 
inflammation 
scores) 
according 
to 
NAS 
scoring 
and 
steatosis-activity-fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to NAS scoring and with at least 
1 point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum of 
ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
• 
To assess the following endpoints at Week 72, and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset of: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 
 
Exploratory endpoints 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Study Duration (planned): estimated 96 months (First Patient First Visit [FPFV]-Last Patient Last Visit 
[LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: March 2016 – Sep 2018 
• 
Recruitment period: March 2016 – May 2020 
• 
FPFV: March 2016 
• 
Surrogate endpoint analysis: Q1 2020 – Q2 2020 
• 
LPLV (LTTP): estimated within Q1 2024 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will also review the interim analysis results and provide final recommendations regarding trial 
termination due to futility and adjustment of the target number of primary events. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, cardiologist, hepatologist, 
oncologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 


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Clinical Events Committee (CEC) 
The CEC will conduct the adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint, all Drug-Induced Liver Injury events, and all Major Cardiovascular Events as 
defined in the CEC charter. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, 1 endocrinologist, and 3 histopathologists all 
of whom will be independent of the participants in the study. 
 








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reading process can be expedited allowing a shorter time between SV1 or SV2 and V1. Coagulation (platelet count and PT [INR]) should be checked locally prior to 
this liver biopsy (according to local medical standards in each hospital). 
 
Randomization visit can be scheduled as soon as all the results are available to confirm the eligibility of the patients. 
5. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to 
Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
6. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
7. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control). 
9. 
The maximum time period between visits in the Long-term Treatment Period (LTTP) is to be 192 days due to the study drug supply provided to the patient. 
10. In the LTTP the first ECG will be performed at V9 and then every 48 weeks. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the LTTP (following approximately 96, 120, and 168 weeks of treatment, respectively), 
and every 48 weeks thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 
14. Ultrasonographic exam will be performed at V1 then approximately every year (at V5, V8, V10, V12…). Where possible ultrasonographic exam must be done at the day of visit. 
Otherwise, it can be performed within 7 days around the visit date. 








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4.
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13).
5.
Whole blood sample will be only taken at SV1 while plasma and serum samples are to be taken at every visit ONLY for patients who have signed the pharmacogenomic and
biomarker ICF.
6.
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 6 months of planned Randomization visit (V1) are available, then SV1 and
V1 must be scheduled at least 8 weeks apart in order to have 2 consecutive values for DILI adjudication. In any case, the visits should be scheduled in order to obtain the needed
results prior to the randomization.
7.
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy.
8.
AFP and osteocalcin to be tested every year (V1, V5, V8, V10, V12, V14...).


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................ 6 
STUDY CONTACTS .............................................................................................................................. 7 
SUMMARY OF CHANGES ...................................................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ............................................................................................................... 21 
TABLE OF CONTENTS ....................................................................................................................... 39 
TABLE OF TABLES ............................................................................................................................ 45 
TABLE OF FIGURES .......................................................................................................................... 46 
LIST OF ABBREVIATIONS .................................................................................................................. 47 
1. 
INTRODUCTION ................................................................................................................. 50 
1.1. 
NONALCOHOLIC STEATOHEPATITIS .................................................................................... 50 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 50 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 52 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................. 53 
1.4.1. 
Pharmacology .......................................................................................................... 53 
1.4.2. 
Safety pharmacology ................................................................................................ 53 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 53 
1.4.4. 
Toxicology ............................................................................................................... 55 
1.4.4.1. 
Mutagenicity and genotoxicity ..................................................................................................... 55 
1.4.4.2. 
Acute toxicity .................................................................................................................................. 55 
1.4.4.3. 
Repeated dose toxicity studies .................................................................................................... 55 
1.4.4.4. 
Phototoxicity studies ..................................................................................................................... 55 
1.5. 
CLINICAL STUDIES ............................................................................................................. 56 
1.5.1. 
NASH ...................................................................................................................... 56 
1.5.2. 
Primary Biliary Cholangitis (PBC) ............................................................................... 57 
1.6. 
CONCLUSION ..................................................................................................................... 57 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................. 57 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE ............................................................................. 58 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT ................................................................................. 59 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 59 
1.9.2. 
Primary endpoint for clinical outcome (post-approval confirmation) .............................. 59 
1.10. RATIONALE FOR STUDY DURATION ..................................................................................... 60 


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1.11. RATIONALE FOR SAFETY MONITORING ............................................................................... 60 
2. 
TRIAL OBJECTIVES ............................................................................................................. 62 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 62 
2.1.1. 
Surrogate endpoint analysis ...................................................................................... 62 
2.1.2. 
Long-term endpoint ................................................................................................. 62 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS .................................. 62 
2.3. 
OTHER SECONDARY OBJECTIVES ........................................................................................ 63 
2.4. 
EXPLORATORY OBJECTIVES ................................................................................................ 64 
2.5. 
EXPLORATORY -OBJECTIVES -FOR -F1 -GROUP -AND -THE -OVERALL –POPULATION 
(WHATEVER THE FIBROSIS STAGE – F1, F2 OR F3) .............................................................. 64 
2.6. 
SAFETY SECONDARY OBJECTIVES ....................................................................................... 64 
3. 
TRIAL DESIGN .................................................................................................................... 65 
3.1. 
NUMBER OF PATIENTS ....................................................................................................... 65 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................... 65 
3.3. 
DOSE ADJUSTMENT CRITERIA ............................................................................................. 66 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................ 66 
3.5. 
STUDY PERIODS ................................................................................................................. 66 
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1) ...................................................................... 66 
3.6.1. 
Screening visits SV1 and SV2: ................................................................................... 66 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended Week -4): ....... 68 
3.6.3. 
Screening Phone Visit SPV (Week -1): ........................................................................ 68 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) .............................................................. 68 
3.7.1. 
Randomization Visit V1 (Week 0): .............................................................................. 69 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): ....................................... 69 
3.8. 
LONG-TERM TREATMENT PERIOD ....................................................................................... 70 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) ............................................................. 71 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ............................................... 72 
3.9. 
END OF STUDY TREATMENT VISIT ...................................................................................... 72 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 73 
3.11. OPTIONAL VISITS .............................................................................................................. 74 
3.11.1. 
Retesting screening visits .......................................................................................... 74 
3.11.2. 
Unscheduled visits ................................................................................................... 74 
3.11.3. 
Specific monitoring ................................................................................................... 74 
3.12. OFF-SITE STUDY PROCEDURES IN CASE OF CRISIS SITUATION ............................................ 75 
3.12.1. 
Safety and drug compliance procedures ..................................................................... 75 
3.12.2. 
Local lab assessment ................................................................................................ 76 
3.12.3. 
Delivery of study treatment to the patient .................................................................. 76 
3.12.4 
Completion of Missed Study Procedures ..................................................................... 76 
3.13 EXPLORATORY/ANCILLARY SUBSTUDY ......................................................................... 77 


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4. 
PATIENT SELECTION .......................................................................................................... 78 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 78 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 79 
5. 
TRIAL PROCEDURES ........................................................................................................... 82 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ....................................... 82 
5.1.1. 
Standard diet and exercise recommendations ............................................................. 82 
5.1.2. 
Dietary, fluid, and lifestyle restrictions ....................................................................... 82 
5.1.3. 
Home pregnancy test for women of childbearing potential ........................................... 83 
5.1.4. 
Sun exposure .......................................................................................................... 83 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 83 
5.2.1. 
Handling of patient withdrawal .................................................................................. 83 
5.2.2. 
Permanent discontinuations of study drug .................................................................. 83 
5.2.3. 
Patient discontinuation from the Study ....................................................................... 84 
5.2.4. 
Patients lost to follow-Up .......................................................................................... 85 
5.2.5. 
Replacement ........................................................................................................... 85 
5.2.6. 
Premature discontinuation of the study ...................................................................... 85 
5.3. 
PATIENT RESCREENING ...................................................................................................... 86 
6. 
ASSESSMENTS ................................................................................................................... 87 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ................................................................................. 87 
6.1.1. 
Histological assessments ........................................................................................... 87 
6.1.1.1. 
Recommendations related to liver biopsy .................................................................................. 87 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score .................................................... 88 
6.1.2. 
Biological assessments ............................................................................................. 88 
6.1.2.1. 
Laboratory assessments ............................................................................................................... 89 
6.1.2.2. 
Urinary pregnancy tests ................................................................................................................ 89 
6.1.2.3. 
Serology (SB1) ............................................................................................................................... 89 
6.1.2.4. 
Other parameters .......................................................................................................................... 89 
6.1.3. 
Constitution of biobank ............................................................................................. 89 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 90 
6.2.1. 
Physical examination ................................................................................................ 90 
6.2.2. 
Waist circumference ................................................................................................. 90 
6.2.3. 
Vital signs ............................................................................................................... 90 
6.2.3.1. 
Important points for clinical blood pressure measurement ..................................................... 90 
6.2.4. 
Electrocardiogram .................................................................................................... 91 
6.2.5. 
FibroScan ................................................................................................................ 91 
6.2.6. 
Quality of life questionnaire ...................................................................................... 91 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ......................................................................................................................................... 92 
6.3.1. 
Creatine phosphokinase ............................................................................................ 92 


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6.3.2. 
Liver function monitoring .......................................................................................... 92 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values .................................. 92 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values ............................. 93 
6.3.3. 
Threshold for diagnosis of cirrhosis ............................................................................ 94 
6.4. 
SAFETY & EFFICACY DATA REVIEW ..................................................................................... 94 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................. 94 
6.6. 
GUIDANCE FOR INVESTIGATORS ......................................................................................... 95 
6.6.1. 
Summary of safety data............................................................................................ 95 
6.6.2. 
Safety data conclusion .............................................................................................. 97 
6.6.3. 
Benefit/risk assessment ............................................................................................ 98 
7. 
TREATMENTS ..................................................................................................................... 99 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS .............................................................................. 99 
7.2. 
PACKAGING AND LABELING ................................................................................................ 99 
7.2.1. 
Packaging ............................................................................................................... 99 
7.2.2. 
Labeling .................................................................................................................. 99 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ....................................... 100 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP ................................................. 100 
7.5. 
STORAGE CONDITIONS .................................................................................................... 100 
7.6. 
DISPENSING OF TREATMENT ............................................................................................ 100 
7.7. 
TREATMENT REPLACEMENT .............................................................................................. 101 
7.8. 
PROCEDURE FOR BLINDING .............................................................................................. 101 
7.9. 
PROCEDURE FOR UNBLINDING ......................................................................................... 101 
7.10. STUDY DRUG COMPLIANCE ............................................................................................... 102 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................ 102 
7.12. OTHER MEDICATION ........................................................................................................ 102 
7.12.1. 
Handling of concomitant medication ........................................................................ 102 
7.12.2. 
Non-permitted medication ...................................................................................... 103 
7.12.3. 
Permitted medication under condition ...................................................................... 103 
7.12.4. 
Permitted medication ............................................................................................. 104 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................. 105 
8.1. 
DEFINITIONS ................................................................................................................... 105 
8.1.1. 
Adverse events ...................................................................................................... 105 
8.1.2. 
Adverse event of special interest (AESIs) ................................................................. 106 
8.1.3. 
Serious adverse events ........................................................................................... 107 
8.1.3.1. 
Life-threatening adverse events ................................................................................................ 107 
8.1.3.2. 
Inpatient or prolonged hospitalization ...................................................................................... 107 
8.1.3.3. 
Significant or incapacitating disability ....................................................................................... 108 
8.1.3.4. 
Medically important conditions .................................................................................................. 108 
8.1.4. 
Clarification on serious adverse events: .................................................................... 108 


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8.1.5. 
Adverse drug reaction ............................................................................................ 109 
8.1.6. 
Unexpected adverse event ...................................................................................... 109 
8.2. 
ASSESSMENTS ................................................................................................................. 109 
8.2.1. 
Intensity assessment .............................................................................................. 109 
8.2.2. 
Relation to the study treatment ............................................................................... 109 
8.2.3. 
Action taken and outcome ...................................................................................... 110 
8.3. 
REPORTING ..................................................................................................................... 111 
8.3.1. 
Reporting an adverse event .................................................................................... 111 
8.3.2. 
Reporting a serious adverse event or an adverse event of special interest ................... 111 
8.3.3. 
Follow-up .............................................................................................................. 113 
8.4. 
POST STUDY REPORTING REQUIREMENTS ......................................................................... 113 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS ............................................................................ 113 
8.6. 
SPECIAL SITUATION REPORTS .......................................................................................... 114 
8.6.1. 
Pregnancy ............................................................................................................. 114 
8.6.2. 
Medication error..................................................................................................... 114 
8.6.3. 
Misuse .................................................................................................................. 114 
8.6.4. 
Overdose .............................................................................................................. 115 
8.6.5. 
Abuse ................................................................................................................... 115 
9. 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 116 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .............................................................. 116 
9.2. 
ENDPOINTS ..................................................................................................................... 116 
9.2.1. 
Surrogate endpoint - resolution of NASH .................................................................. 116 
9.2.2. 
Long-term endpoint – time to clinical event/death .................................................... 116 
9.2.3. 
Key Secondary Endpoints ........................................................................................ 117 
9.2.4. 
Other Secondary Endpoints ..................................................................................... 117 
9.2.5. 
Exploratory endpoints ............................................................................................. 119 
9.3. 
ANALYSIS SETS ................................................................................................................ 119 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS .................................................................................. 119 
9.4.1. 
Resolution of NASH ................................................................................................ 119 
9.4.2. 
Long-term endpoints .............................................................................................. 120 
9.5. 
OTHER STATISTICAL ANALYSIS ......................................................................................... 120 
9.5.1. 
Key secondary endpoint.......................................................................................... 120 
9.5.2. 
Other secondary endpoints ..................................................................................... 121 
9.5.3. 
Subgroup analyses ................................................................................................. 121 
9.5.4. 
Exploratory analyses .............................................................................................. 122 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR .......................................................................... 122 
9.7. 
SAMPLE SIZE CALCULATION .............................................................................................. 122 
9.7.1. 
Resolution of NASH ................................................................................................ 122 


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9.7.2. 
Time to clinical event/death .................................................................................... 123 
9.8. 
SAFETY ANALYSIS ............................................................................................................ 124 
9.8.1. 
Surrogate endpoint analysis .................................................................................... 124 
9.9. 
INTERIM ANALYSIS .......................................................................................................... 125 
10. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 126 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ................................................................ 126 
10.2. RETENTION OF RECORDS ................................................................................................. 126 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 128 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ............................................................. 128 
11.2. ETHICAL PRINCIPLES ........................................................................................................ 129 
11.3. QUALITY ASSURANCE ....................................................................................................... 129 
12. 
ETHICS AND REGULATORY................................................................................................ 130 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 130 
12.2. COMPETENT AUTHORITY .................................................................................................. 131 
12.3. PATIENT INFORMATION AND CONSENT ............................................................................. 131 
12.4. PATIENT CONFIDENTIALITY .............................................................................................. 131 
12.5. DEFINITION OF THE END OF THE RESEARCH ..................................................................... 132 
13. 
FINANCING AND INSURANCE ............................................................................................ 133 
13.1. FINANCIAL ISSUES ........................................................................................................... 133 
13.2. INSURANCE AND PATIENT INJURY .................................................................................... 133 
14. 
STUDY RESULTS AND PUBLICATION POLICY ...................................................................... 134 
14.1. STUDY REPORT ................................................................................................................ 134 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION................................................................................................................... 134 
15. 
REFERENCES LIST ............................................................................................................ 136 
APPENDICES .................................................................................................................................. 139 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................ 140 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................ 148 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ............................................................... 149 
APPENDIX IV: ALCOHOL COMPARISON TABLE .................................................................................. 151 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING ................................................................. 152 
 
 
 


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TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE 
29 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE 
33 
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients treated with 
elafibranor) by system organ class (SOC) reported in completed elafibranor clinical studies with 
repeated administration of elafibranor (at least 14 days) from 80 mg/day up to 300 mg/day 
(MTD) 
96 
 


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TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
37 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
38 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest  
AFP 
Alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase 
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
DSMB 
drug-induced liver injury 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FITT 
full intent-to-treat set 
FLI 
fatty liver index 
FPFV 
first patient first visit 


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FSS 
full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP-1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IQR 
InterQuartile Range 
IR 
Insulin Resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
LTTP 
Long-term Treatment Period 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model End stage Liver Disease 
NAFL 
 
nonalcoholic fatty liver  
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
PBC 
National Cholesterol Education Program’s Adult Treatment Panel III  
Primary Biliary Cholangitis 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 


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SAF 
Steatosis - activity - fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reaction 
SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
UDCA 
Tumor Necrosis Factor-alpha 
UrsoDeoxyCholic Acid 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases (ATs), 49% in morbidly obese patients, and 67% in a subset of patients with incident 
chronic liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 
16% in Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome, and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop that leads to 
fibrogenesis. collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 
Adiponectin decreases fatty acid oxidation and inhibits hepatic 
gluconeogenesis.7 Both human and mouse models have demonstrated that lower adiponectin levels are 
associated with increased severity of hepatic inflammation.8,9 Tumor Necrosis Factor (TNF)α is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 
Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 


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proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia, insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 
Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory macrophages.17,18 These studies demonstrate that PPARδ encourages 


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macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raises the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. Pharmacology 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. Briefly, in experimental models of type 2 diabetes, elafibranor 
has insulin-sensitizing and glucose lowering properties. In db/db mice, a 28-day treatment with elafibranor 
produced a dose-dependent decrease in fasting plasma glucose and glycated hemoglobin (HbA1c), 
comparable to the effect of rosiglitazone. However, in contrast to the PPARγ reference agonist, elafibranor 
did not increase plasma adiponectin, thus ruling out a PPARγ -mediated effect on adipose tissues. Similarly, 
in ob/ob mice, elafibranor ameliorated plasma glucose and insulin levels without modulating plasma 
adiponectin or inducing PPAR target genes in adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 
target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 


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the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 
elafibranor (GFT505) has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig, 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 


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1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 
1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 


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1.5. 
CLINICAL STUDIES 
1.5.1. 
NASH 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 completed clinical trials, and 5 still ongoing. A total of 561 healthy lean subjects, 
60 overweight or obese subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 
20 with hepatic impairment (Child-Pugh class A, B or C) have been randomized to date in the completed 
trials. Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 
A Phase 2 program was initiated to assess the safety and efficacy profile of elafibranor in subjects with 
cardiometabolic disorders and NASH. To date, 5 Phase 2a studies have been completed, in which 
297 subjects were randomized: 37 with mixed hyperlipidemia (type IIb Frederickson); 94 with atherogenic 
dyslipidemia and abdominal obesity; 47 with impaired glucose tolerance and abdominal obesity; 97 with 
diabetes mellitus type II; and 22 with insulin resistance and abdominal obesity. A Phase 2b study has also 
been completed, in which 274 subjects with NASH were randomized. In the Phase 2 program, the 
elafibranor daily doses ranged between 30 mg and 120 mg, with a maximum treatment duration of 
12 months.  
A Phase 2a randomized, open-label, sequential cohort study (GFT505E-218-1) will assess the PK and 
pharmacodynamic (PD) profile and the safety and tolerability of two dose levels of GFT505 (80 mg and 
120 mg) in children and adolescents, 8 to 17 years of age, with NASH. In this study, subjects will receive 
80 or 120 mg of GFT505 once daily for 12 weeks. The study consists of two paediatric patient cohorts with 
NASH which will be dosed sequentially. Cohort 1 will consist of +/- 12 subjects who are ≥12 to ≤17 years 
of age. Once 10 subjects in cohort 1 have been evaluated for PK and safety through Visit 4 (30 days) by an 
independent Data Safety Monitoring Board (DSMB), enrollment will be open to subjects ≥8 to ≤11 years of 
age. Cohort 2 will consist of +/- 8 subjects who are ≥8 to ≤11 years of age.  
At time of DSUR data lock point (31 July 2019), 1 subject (≥12 to ≤17 years of age) had been enrolled 
and exposed to at least one administration of GFT505. 
A Phase 2 study (GFT505-219-8) to evaluate the effect of a 6-week elafibranor (120 mg) treatment 
administered once daily on hepatic lipid composition in subjects with nonalcoholic fatty liver (NAFL) is 
currently ongoing. This study intends to achieve mechanistic information about the mode of action of 
elafibranor on the (lipid) metabolism in the human fatty liver. Subjects with NAFL will receive 120 mg of 
GFT505 or placebo once daily for 6 weeks in randomized order in a crossover design. Overall, 16 subjects 
with NAFL are intended to be included. 
For additional information see Investigator’s Brochure. 


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1.5.2. 
Primary Biliary Cholangitis (PBC) 
Based on the mechanism of action of elafibranor, and on the relevant efficacy and safety data collected to 
date, specifically on decrease in ALP and inflammation markers, a Phase 2a study has been launched in 
PBC has been completed, under IND 132202, filed in September 2016. The aim of this study was to 
validate the efficacy of elafibranor on ALP decrease in this patient population, and to confirm its safety in a 
population with PBC. This study was designed to compare the effect of daily oral administration for 
12 weeks of GFT505 80 mg and 120 mg on changes in serum alkaline phosphatase (ALP) to that of 
placebo in subjects with PBC and inadequate response to ursodeoxycholic acid (UDCA). 
For additional information see Investigator’s Brochure. 
 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers.  
Moreover at the last DSUR cut-off date (31 July 2019), 25 clinical studies with elafibranor have been 
conducted or are ongoing (in which a total of 3245 subjects have been randomized, including an estimated 
2206 subjects exposed to elafibranor. In general, the treatment was well tolerated. No interaction, 
medication errors, or abuse/misuse cases have been reported to this date. See Section 6.6 “Guidance for 
investigators” for further information. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrates that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis, and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 


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Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature,21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 
As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 


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1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only 
(i.e., nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the 
basis for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely 
embraced by the academic community and expressed in several scientific society endorsed position 
papers.29,30 Based on the recently published recommendations from this workshop,30 resolution of NASH 
with no worsening of fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling 
patients with NASH and fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is 
related to liver-related mortality,22 the “no worsening of fibrosis” should be no progression of one stage in 
fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (post-approval confirmation) 
The primary endpoint of the Long-term Treatment Period (LTTP) of the study is to evaluate the effect of 
elafibranor on the progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes as 
measured by the onset of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15 for patients with baseline MELD score ≤12, and hospitalization due to occurrence of hepatic 
encephalopathy defined as West Haven/Conn score ≥2 or variceal bleeding, spontaneous bacterial 
peritonitis, and uncontrolled ascites requiring treatment). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 


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Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a post-approval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the LTTP is based on a 7% probability of patients with NASH and moderate and 
advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as determined from recently 
published data 21,22,23,24,25 and the available data of the mortality risk in this patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to non-primates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine, modification of diet in renal disease (MDRD) derived 
estimated glomerular filtration rate (eGFR), and the results of urinalysis (dipstick) will be reported at each 
visit, as well as blood urea nitrogen. The other markers (plasmatic or urinary) will be assayed in batch and 


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will be reviewed on an ongoing basis through regular safety reviews by the DSMB which includes a 
nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be routinely monitored 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total and 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 
During the LTTP, patients will be monitored by clinical and biological assessment. A FibroScan 
measurement and noninvasive markers assessment will be performed every 24 weeks, and if cirrhosis is 
suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
To assess the efficacy and safety of elafibranor as compared to placebo in adult NASH patients with fibrosis 
stage 2 or 3 (F2-F3), the primary and secondary objectives are as follows: 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint analysis 
To evaluate the efficacy of elafibranor 120 mg QD for 72 weeks versus placebo on resolution of NASH 
without worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least 1 stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a 
composite endpoint composed of death due to any cause, histological liver cirrhosis, and the full list of 
portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 for patients with baseline MELD score ≤12 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization, 
o 
spontaneous bacterial peritonitis, 
o 
ascites requiring treatment, 
2.2. 
KEY SECONDARY OBJECTIVES – AT SURROGATE ENDPOINT ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of surrogate endpoint analysis, on 
the following endpoint: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 


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• 
Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, 
HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 
o 
percentage of patients with at least a 1 point improvement in histological scores 
(NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), 
or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and 
steatosis-activity-fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 
1 point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to SAF scoring and with at least 
1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 


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o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36] questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events  
o 
cardiovascular events 
o 
liver-related death events 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY -OBJECTIVES -FOR -F1 -GROUP -AND -THE -OVERALL –POPULATION 
(WHATEVER THE FIBROSIS STAGE – F1, F2 OR F3) 
• 
To explore, in F1 patients and in the overall population whatever the fibrosis stage (F1, F2 or F3), 
the same endpoints as for the primary and secondary objectives. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg: 
• 
SAE, AE, AESI, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver markers 
• 
renal biomarkers (including urinalysis) 
• 
cardiac biomarkers 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. 
The first double-blind 72-week Treatment Period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the surrogate endpoint efficacy analysis, followed by a 
LTTP to assess efficacy on progression to cirrhosis, all-cause mortality, and liver-related clinical outcomes 
as measured by the onset of any of the listed adjudicated events (see Section 2.1.2). The study will 
terminate upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed 
in the composite endpoint for long term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by 
type 2 diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with 
fibrosis stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of 
NASH will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize at least 2022 F2/F3 patients to either active (1348 patients) or placebo 
(674 patients) treatment in a 2:1 ratio. Up to 202 additional patients (a maximum level of 10% of the 
F2/F3 enrolled patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients 
with at least 2 of the following conditions: persistent elevated (absence of normal ALT within the past year, 
obesity defined by a body mass index (BMI) ≥30, metabolic syndrome [National Cholesterol Education 
Program’s Adult Treatment Panel III {NCEP ATP III definition}], type 2 diabetes, or HOMA-IR >6) will also 
be enrolled, and followed as an exploratory group. The F1 patients will not be included in the primary 
surrogate endpoint and final analysis or in the sample size calculation (detailed in Section 9.7). As such a 
total of at least 2224 patients will be enrolled, including the exploratory F1 group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 
2:1 ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 


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•
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients).
Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 96 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (LTTP). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a LTTP up to the occurrence of a prespecified number of events. 
Study procedures are summarized in Table 2, and Figure 1. 
Schedule: 
•
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV).
•
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to
V7).
•
Week 72 to end of study (EOS): LTTP with elafibranor or placebo until 456 patients experience an
event listed in Section 2.1.2 “ Long-term endpoint”(visits V8 to Vn).
3.6. 
SCREENING PERIOD (WEEK -12 TO WEEK -1)
3.6.1. 
Screening visits SV1 and SV2: 
The following screening procedures will be performed for all potential patients at SV1 conducted during the 
screening period and prior to Randomization: 
•
Signature of informed consent witnessed by the Investigator or designated person. Note: The 
signature of the informed consent may also be performed before SV1.
•
Patient number allocation via IXRS.
•
Check medical history/demographics.
•
Check inclusion/exclusion criteria (described in Section 4).
•
Physical examination (described in Section 6.2.1).


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•
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits.
•
Record vital signs (described in Section 6.2.3).
•
Record height, weight, and waist circumference.
•
Check concomitant/prior medication (within 6 months prior to Screening) (described in 
Section 7.12 and APPENDIX III: Permitted/non-permitted medication)
•
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the Screening Visit.
•
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8).
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of SV1) is available, it is recommended to schedule an 
additional SV2 visit at least Week -4 prior to the planned Randomization V1 in order to obtain the results in 
time. 
The following biological assessments 
•
Blood samples (described in Table 2).
•
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed).
•
Urinalysis dipstick.
•
Urinary pregnancy test (for women of childbearing potential only [WOCBP]).
If no historical values of AST, ALT, total bilirubin and INR meeting the requirements of within 8 weeks to 
6 months of randomization visit are available, then SV1 and V1 must be scheduled at least 8 weeks apart 
in order to have 2 consecutive values for DILI adjudication. 
In case of known cured hepatitis C virus (HCV) infection, HCV RNA testing can be done at SV1 without 
waiting for HCV Ab results. 
If needed, a retesting of abnormal HbA1c, or creatine phosphokinase (CPK) results or additional testing of 
HCV RNA, may be performed during the screening window to determine the eligibility for the study as 
described in exclusion criteria 5, 12, 32, and 33 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who has signed the ICF will be allocated a 
patient number composed of 9 digits which is generated by the IXRS. 

First 3 digits corresponding to the ISO numeric country code (this number will be predefined),

Next 3 digits corresponding to the site number (this number will be predefined),

Last 3 digits corresponding to the numerical order of the patient entry at the study site.


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to recommended 
Week -4): 
If no diagnostic liver biopsy within 6 months of SV1 is available, it is recommended to schedule an 
additional SV2 visit at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in 
Section 6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/non-inclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Screening (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during 
the Screening Period) with: 
•
Presence of NASH, with at least a score of 1 in each component of the NAS (steatosis scored 0 to
3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND NAS ≥4.
•
Fibrosis stage 2 and 3.
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When at least the first 1023 randomized patients (F2-F3) complete Week 72 (or discontinue early from the 
study treatment), a surrogate endpoint analysis will be performed and potentially filed for initial market 
approval under Subpart H or conditional approval, (see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (surrogate endpoint analysis). The 
patient will be contacted at least 1 week before each visit to be reminded of procedures and investigational 
product (IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
•
Check inclusion/exclusion criteria (detailed in Section 4).
•
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS.
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in
Section 5.1.2), and tobacco habits


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•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III:
Permitted/non-permitted medication)
•
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.6)
•
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in
Section 6 and Section 8)
•
Study placebo or drug dispensation (described in Section 7.6)
•
Blood samples (described in Table 2)
•
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed)
•
Urinalysis and urinary dipstick (described in Table 2)
•
Urinary pregnancy test (for WOCBP only)
•
Provision of home pregnancy test kits (for WOCBP only)
•
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since
previous visit (for WOCBP only, every visit from V1)
•
Record waist circumference (V1, V3, V5, and V7, only)
•
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.4)
•
FibroScan (V1 and V7 only, described in Section 6.2.5)
•
Drug accountability (every visit from V2).
•
Ultrasonography of bladder and urinary tract (at V1 and V5 only) (described in Section 0).
Additional procedures to be performed at V7 are: 
•
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation.
•
Blood samples for coagulation taken (platelets count and prothrombin time [PT (INR)]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy.
•
Ultrasonographic exam will be performed at V1 then approximately every year (at V5, V8, V10, 
V12…). Where possible ultrasonographic exam must be done at the day of visit. Otherwise, it can 
be performed within 7 days around the visit date.
3.8. 
LONG-TERM TREATMENT PERIOD
The main objective to be evaluated during the LTTP will be the prevention of progression to cirrhosis, 
death due to any cause, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2). 
After the 72-week biopsy, patients will continue in the double-blind LTTP, receiving the same treatment as 
assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by notably measuring the 
appearance of cirrhosis (based on FibroScan measurement associated with biological and/or clinical 
assessments and confirmed by biopsy). 


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At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint described 
in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of the study 
following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the LTTP. The patient will be contacted at least 
1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits
•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication)
•
Quality of life assessment (V8, V9, V11, and every 48 weeks thereafter Section 0)
•
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8)
•
Study placebo or drug dispensation (described in Section 7.6)
•
Blood samples (described in Table 2)
•
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed)
•
Urinalysis and urinary dipstick (described in Table 2)
•
Urinary pregnancy test (for WOCBP only)
•
Provision of home pregnancy test kits (for WOCBP only)
Record result of home pregnancy tests (to be performed every 4 weeks [see 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL]) 
•
since previous visit (for WOCBP only, every visit from V1)
•
Record waist circumference
•
12-lead ECG (every 48 weeks from V9; described in Section 6.2.4)
•
FibroScan (described in Section 6.2.5)
•
Drug accountability
•
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation
•
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and
tested at a local laboratory prior to the liver biopsy.
•
Ultrasonography of bladder and urinary tract (at V8 then every year [V10, V12…]) (described in
Section 6.2.5).


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3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on diet and 
lifestyle, concomitant medications, clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the Investigator may 
decide to perform an unscheduled visit (described in Section 3.11.2). IXRS registration will be performed 
for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in 
Section 1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate 
efficacy outcomes and safety through phone call visits every 24 weeks as described in Section 3.10 and 
Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 2, Figure 1, and Figure 2. 
The patient will be contacted at least 1 week before the visit to be reminded of procedures and IP return 
(if required). The following procedures will be performed at the EOT Visit: 
•
IXRS registration
•
Physical examination (described in Section 6.2.1)
•
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.3)
•
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and 
APPENDIX II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in 
Section 5.1.2), and tobacco habits
•
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.12 
and 
APPENDIX 
III: 
Permitted/non-permitted medication)
•
Quality of life assessment (described in Section 0)
•
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8)
•
Blood samples (described in Table 2)
•
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed)
•
Urinalysis and urinary dipstick (described in Table 2),
•
Urinary pregnancy test (for WOCBP only)


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• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.4) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following 
the EOT Visit and have no further follow-up, unless the patient experiences at the time of EOT visit, an 
ongoing adverse event possibly related to study treatment for which the follow-up should last until 
resolution of this adverse event.. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with phone visits every 24 weeks (±2 weeks from EOT Visit) following 
the EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 


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o 
MELD score ≥15 for patients with baseline MELD score ≤12 
o 
the onset of: 
 
variceal bleed requiring hospitalization 
 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization 
 
spontaneous bacterial peritonitis 
 
ascites requiring treatment 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are:  
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
• 
HCV RNA testing: in case positive HVC Ab test at SV1 required latest 2 weeks prior to 
Randomization (V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1).  
Any other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitors. 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the screening period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.11.3. 
Specific monitoring 
If the conditional approval for elafibranor is not obtained upon submission of interim analysis results, 
patients will be asked to come back for a specific monitoring visit every year over 4 years after the end of 
the long term treatment period. 


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These specifics visits will include: dosage of alpha-fetoprotein (AFP) and osteocalcin, urine 
cytology, and ultrasonography of urinary tracts and bladder. 
3.12. OFF-SITE STUDY PROCEDURES IN CASE OF CRISIS SITUATION  
 Based on assessment of risk, and to ensure patient safety and minimize risks to trial integrity, the sponsor 
determined that the following optional off-site study procedures can be performed in case a study 
participant cannot attend an on-site visit during the COVID-19 crisis:  
• 
Safety assessment via phone call  
• 
Local lab assessment 
• 
Delivery of the study treatment to patient 
• 
Visit to patient’s home  
These options apply to all on-site study visits except for the randomization visit (Visit 1).  Visit 1 must occur 
on-site as per section 3.7.1 
These solutions can be applied depending on the investigator’s judgment of each case and the patient’s 
agreement. The alternative solutions can be implemented in response to the COVID-19 crisis prior to the 
notification or submission to and approval of regulatory agencies and ethics committees. 
Before implementing any of these options for a patient, the site will contact the patient to check whether 
he/she agrees with the off-site procedures. 
The patient will be invited to attend an on-site visit to complete the study procedures as per protocol, as 
soon as the situation allows it. 
In cases of any future emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure 
patient safety and minimize risks to trial integrity, after completion of a risk assessment similar measures 
could be taken. 
3.12.1. 
Safety and drug compliance procedures 
The following procedures will be performed via either a phone contact, or, if safe and possible, a direct 
visit to the patient: 
• 
Check for AEs and occurrence of any clinical outcome (described in Section 6 and 
Section 8) 
• 
Report any change in diet and life style factors  
• 
Check concomitant/prior medication (described in Section 7.12 and 
APPENDIX III: Permitted/non-permitted medication) 


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• 
Record result of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) 
since previous visit (for WOCBP only, every visit from V1) 
• 
Drug accountability  
o 
dates of any study drug interruption since the last dispensation and reason* 
o 
end of treatment (if applicable): date of last dose of study drug and reason* 
o 
end of study (if applicable) : date of end of study and reason* 
*if the reason is related to an AE, collect all required details 
• 
Physical examination if possible with a direct visit to the patient (described in Section 6.2.1)  
• 
Record vital signs and weight if possible with a direct visit to the patient (described in Section 6.2.1 
and Section 6.2.3)  
• 
Based on the study visit period for the patient, excluding the quality of life assessment, additional 
protocol related procedures of Section 3.7.2 or Section 3.8.1 may be performed if possible and if 
necessary conditions are met 
3.12.2. 
Local lab assessment  
The patient will be asked if he/she can access a local lab in the few days after the phone contact to obtain 
hematology, biochemistry and urinalysis testing.  
 
If a direct visit to the patient is safe and possible, the appropriate lab parameters corresponding to the 
on-site study visit as described in Table 2 will be collected. 
3.12.3. 
Delivery of study treatment to the patient 
The IXRS registration will be completed to trigger study drug kit assignments, and the assigned drug kits 
can be shipped to the patient, or delivered directly to the patient by the site study staff if safe and 
possible. 
As per the usual study visit, the patient will be instructed to continue taking the available tablets from the 
existing kit until he/she receives the new kit. 
 
The study drug compliance and study drug accountability will be performed as described in Section 7.10 
and Section 7.11 once brought to the study site/study pharmacy. 
3.12.4 
Completion of Missed Study Procedures 
As soon as the situation allows it, the site will schedule the patient’s on-site visit to complete the missed 
study procedures (those that could not be performed during the phone calls/visit to patient) as per 
protocol (see Section 3.7.2 or Section 3.8.1).  


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3.13 EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below: 
o 
Cessation of menses for at least 12 months due to ovarian failure,  
o 
Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure  
o 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient) 
o 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner, or intra-uterine device) 
o 
Double contraception with barrier AND highly effective hormonal method of contraception 
(oral, intravaginal, or transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation; oral, injectable, or implantable 
progestogen-only hormonal contraception associated with inhibition of ovulation; or 
intrauterine hormone-releasing system). The hormonal contraception must be started at 
least 1 month prior to Randomization. 
4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in 
each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular 
inflammation scored 0-3). 
5. NAS ≥4. 
6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system.  
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS ≥5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal 
ALT within the past year), obesity defined by a BMI ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or HOMA-IR >6. 
7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:  


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o 
1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy 
within 6 months before screening is available) 
o 
1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on 
NASH 
o 
a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy 
has already been performed within the past year 
o 
1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological 
confirmation. 
8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty 
acids (>2 g/day), or UDCA; a stable dose from at least 6 months prior to diagnostic liver biopsy is 
required. 
9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: 
o 
no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization 
(i.e., implementation of a new anti-diabetic therapy) for patients treated with metformin, 
gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like 
peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 
6 months prior to diagnostic liver biopsy, except for GLP-1 agonists, which must remain on 
stable dose in the 6 months prior to diagnostic liver biopsy. 
o 
no implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of treatment 
(V7).  
Initiation of any other antidiabetic drugs is allowed after Randomization based on treating physicians’ 
judgment, except for glitazones which are prohibited 6 months prior to diagnostic liver biopsy until the 
end of treatment. 
10. Patients following adequate life style recommendations 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in 
the course of the study. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients.  
5. Patients with HbA1c >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be 
repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) 
leads to exclusion. 


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6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]), unless the drug was 
discontinued at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial 
infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Pregnant or lactating females or females planning to become pregnant during the study period. 
12. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
Positive hepatitis B surface antigen (HBsAg) 
o 
Positive HCV RNA, (tested for in case of known cured HCV infection, or positive HCV Ab at 
Screening) 
o 
Suspicion of drug-induced liver disease 
o 
Alcoholic liver disease 
o 
Autoimmune hepatitis 
o 
Wilson’s disease  
o 
Primary biliary cirrhosis, primary sclerosing cholangitis 
o 
Genetic homozygous hemochromatosis 
o 
Known or suspected HCC 
o 
History or planned liver transplant, or current MELD score >12. 
13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force applicable to clinical trials. 
14. Patients who cannot be contacted in case of emergency. 
15. Known hypersensitivity to the investigation product or any of its formulation excipients. 
16. Patients with previous exposure to elafibranor. 
17. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug trial or medical device trial containing active substance within 30 days or 
five half-lives, whichever is longer, prior to Screening. 
18. Patients for whom life styles recommendations have never been introduced. 
Concomitant medications (see APPENDIX III: Permitted/non-permitted medication): 


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19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, 
or nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept 
constant for at least 2 months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening and up to end of treatment. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization until end of treatment. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. 
Patients with any history of cancer are excluded except patients with basal cell carcinoma. 
24. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease 
25. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
26. Positive anti-human immunodeficiency virus (HIV) antibody. 
27. AST and/or ALT >10 x upper limit of normal (ULN). 
28. Conjugated bilirubin >1.50 mg/dL due to altered hepatic function. Note: Gilbert Disease patients are 
allowed into the study. 
29. INR >1.40 due to altered hepatic function. 
30. Platelet count <100,000/mm3 due to portal hypertension. 
31. Serum creatinine levels >1.53 mg/dL in males and >1.24 mg/dL in females. 
32. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). 
33. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES
The procedures performed at each visit are summarized in the study schedules (see Table 2, Figure 1, and 
Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will be given at the 
beginning of each patient’s participation and will be maintained throughout the study. These 
recommendations will be based on Therapeutic Lifestyle Change (TLC) counseling (or local equivalent) 
according to NCEP ATP III guidelines. The essential components of TLC and the macronutrient 
recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet and lifestyle 
recommendations 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations. A yes/no response will 
be recorded in the electronic care report form (eCRF). 
5.1.2. 
Dietary, fluid, and lifestyle restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
•
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all
blood sampling. As such, patients should not consume any breakfast or take any medication
(including study medication) in the morning prior the blood sampling. In case the patients do not
fast before a visit, a new appointment will be scheduled within 7 days.
•
On each study visit day, study treatment will be taken under fasting conditions after the blood
sampling (which corresponds to the day of the visit).
•
During the 48 hours preceding each study visit, patients should not perform strenuous exercise.
•
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol).


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• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication). 
5.1.3. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 2 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1). 
5.1.4. 
Sun exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from V1 through to the end of the study (see Section 1.4.4.4). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 


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Some possible reasons that may lead to permanent early study drug discontinuation include: 
•
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2)
•
In the opinion of the Investigator, any AE, AESI, SAE (described in Section 8), or significant 
change in a laboratory value that warrants permanent discontinuation of study drug therapy. 
Investigators are advised to call the Medical Monitor prior to making such a decision
•
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation
•
Non-permitted concomitant medication (described in Section 7.12 and APPENDIX III: 
Permitted/non-permitted medication)
•
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug
•
Non-compliance with the study treatment
•
Uncooperative patient
•
The patient requests to stop study drug permanently.
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit, unless the patient experiences at the time of EOT visit, an ongoing 
adverse event possibly related to study treatment for which the follow-up should last until resolution of this 
adverse event. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, telephone visits 
every 24 weeks (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 


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At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or 
possibly related AEs until the unresolved SAEs or possibly related AEs are judged by the Investigator to 
have stabilized. 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study.  
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 


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If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
5.3. 
PATIENT RESCREENING 
Re-screening is allowed in a screen failed patient if there is a change in the situation of the patient which 
allows him/her to fulfill inclusion/exclusion criteria. This will need sponsor approval. In case of re-screening 
the patient will need to sign a new informed consent and will be entered as a new patient, with a new 
patient number. 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed:  
• 
At baseline 
• 
After 72 weeks of treatment 
• 
After approximately 4 years of treatment (V13) unless a biopsy has been performed within the 
previous year. 
• 
In the case cirrhosis is suspected at any interim visit during the LTPP (based on FibroScan and/or 
clinical and biological assessments)  
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. This will be assessed by the 
investigator according to local practice. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, other 
available slides or new slides to be prepared from an available block of tissue may be requested to the site. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Liverpat, 28 rue de l’amiral Hamelin, 75 116 
Paris– France) where they will be read and scored. Scores for total NAS, steatosis, ballooning, lobular 
inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN scoring system, and 
NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (Cerba Research: Ghent – Belgium, New York – USA, Sydney – 
Australia, or BARC Johannesburg – South Africa) and specific analyses will be performed by another 
laboratory (GENFIT - Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, reportable laboratory results (except serology) will be available at sites approximately 
24 hours after receipt of samples. Final results will be sent to sites. Laboratory reports should be reviewed, 
signed, and dated by the Investigator as soon as they are received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at retesting screening visits) is limited to HbA1c, CPK, and HCV RNA, as described 
Section 3.11. Any other retest deemed necessary by the Investigator should be discussed with the Study 
Medical Monitors. 
In case the lab sampling may not be performed at the scheduled visit, patients should come back to the 
site within 7 days of the visit for lab sampling. 


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6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. At Screening, the Screening Visit 1 chemistry 
panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. It 
is recommended to collect first morning urine samples for urinalysis. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. These tests will also be given to the WOCBP to perform a pregnancy test at home 
every 4 weeks in between visits (see Section 5.1.3). 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (in case of known cured HCV infection, HCV RNA can be tested directly at SV1; otherwise, 
HCV RNA should be tested at a Retesting Screening Visit, only in case HCV ab>0 at SV1 [see 
Section 3.11.1]) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during LTTP, and at the EOT visit. CHI3L1 will only be tested at V1, V7, and V13 (at the time 
of the approximate 4 year biopsy). Alfa-fetoprotein and osteocalcin will be tested every year from V1 up to 
end of study (at V1, V5, V8, V10, V12...). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 


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These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
The patient’s weight will be measured under the same conditions at each visit. Where possible, the scale 
for weight must be the same for a given patient throughout the visits. 
6.2.2. 
Waist circumference 
Waist circumference will be measured at the midpoint between the lateral iliac crest and the lowest rib in 
cm during expiration. The measuring tape should be snug but not compressing the skin and held parallel to 
the floor. The measurement is to be made at normal respiration. 
6.2.3. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.3.1. 
Important points for clinical blood pressure measurement 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 
80% of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and 
the first and last audible sounds should be taken as systolic and diastolic pressure. The column 
should be read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Where possible, the validated 
manometer should be the same for a given patient throughout the visits. 


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6.2.4. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the LTTP starting at V9, and at the EOT visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following 10 minutes rest in the supine 
position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.5. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period and at each visit in the 
LTTP. Where possible, FibroScan must be done at the day of visit. Otherwise, it can be performed within 
7 days around the visit date.  
Recommendations for ensuring a reliable examination are:  
• 
Patient must be fasting for at least 2 hours before the FibroScan examination 
• 
At least 10 consecutive and successful measurements shall be performed without changing probe 
position 
• 
InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, 
to consider a FibroScan measure as reliable. If not, it is recommended to perform a few additional 
individual measures, or to restart the entire FibroScan examination 
Bladder and urinary tract ultrasonography 
Ultrasonography of bladder and urinary tract will be performed every year from V1 up to end of study (at 
V1, V5, V8, Vn…). Where possible ultrasonographic exam must be done at the day of visit. Otherwise, it 
can be performed within 7 days around the visit date. 
6.2.6. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and every 48 weeks thereafter in the LTTP 
until, and including the EOT visit. 


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6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), an additional visit and test within 
3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, muscle 
tenderness and/or marked increase in muscle CPK values (≥3 x ULN and ≤5 x ULN), myopathy must be 
considered and the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, unexplained by strenuous exercise or trauma, the patient must be discontinued from study 
treatment immediately and followed up as described in Section 5.2.2. In case of exercise and/or trauma, 
the CPK should be repeated once weekly to verify decrease of CPK, until CPK lowers to ≤5 x ULN. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
Criteria used for reporting a potential DILI for adjudication are given below and correspond to the 
criteria leading to permanent study drug discontinuation. 
For DILI adjudication, assessment may be performed using as baseline either historical AST, ALT, total 
bilirubin, and INR results meeting the requirements of within 8 weeks to 6 months of planned 
randomization visit (V1), or, using lab results from SV1 and V1 that are at least 8 weeks apart. 
In all cases, whether baseline AT values are normal or elevated, an increase of AT >10 x ULN will lead to 
permanent discontinuation of the patient from study drug, and scheduling of EOT visit (Section 3.9). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline AT values at V1 who at any visit 
from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
If during the following retest: 


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o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (once a week). 
• 
Increase in AT >3 x ULN AND increase in total bilirubin > 2 ULN: permanently discontinue patient 
from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND increase in INR>1.5 (except in case of anticoagulant therapy): 
permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and 
Section 5.2.2). 
• 
Increase in AT >3 x ULN AND fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash: permanently discontinue patient from study drug and schedule EOT Visit (see 
Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x ULN AND eosinophilia (>5%) with total count > ULN: permanently discontinue 
patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.2. 
Monitoring of patients with increased baseline aminotransferase values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to ≤3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but ≤ 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in total bilirubin > 2 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND increase in INR>1.5 (except in case of anticoagulant 
therapy): permanently discontinue patient from study drug and schedule EOT Visit (see Section 3.9 
and Section 5.2.2). 
• 
Increase in AT >3 x baseline value AND fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT Visit 
(see Section 3.9 and Section 5.2.2). 


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• 
Increase in AT >3 x baseline value AND eosinophilia (>5%) with total count > ULN: permanently 
discontinue patient from study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.3. 
Threshold for diagnosis of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the LTTP. 
A liver biopsy may be considered in order to confirm the diagnosis of cirrhosis if during a LTTP visit the 
FibroScan value is ≥ 14 kPa (with IQR/Median stiffness ratio < 30%*) associated with a platelet count 
<150 000/mm3 and at least 1 elevated serum marker of fibrosis indicative of cirrhosis (calculated NAFLD 
fibrosis >0.676 score or reported FIB-4 >2.67). 
*InterQuartile Range (IQR)/Median stiffness ratio (in %) shall remain <30% at the end of the scan, to 
consider a FibroScan measure as reliable. If not, it is recommended to perform a few additional individual 
measures, or to restart the entire FibroScan examination.  
In the case of detection of variceal rupture at endoscopy or of presence of any cirrhosis related event, 
such as MELD ≥15, hepatic encephalopathy, or ascites, then the liver biopsy will not be required for 
diagnosis of cirrhosis, but the diagnosed event will have to be adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY & EFFICACY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. The DSMB will also review the interim analysis results and provide final recommendations 
regarding trial termination due to futility and adjustment of the target number of primary events. A 
detailed description of the interim analysis procedures and decision-making process will be provided in the 
DSMB Charter. 
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 
1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent of the 
participants in the study. The DSMB Charter will define the role, responsibilities, rules, and tasks of the 
DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will conduct adjudication of all disease progression events included in the primary composite 
efficacy long-term endpoint (Section 1.9.2), all DILI events, and all major cardiovascular events as defined 
in the CEC charter. The CEC assessment and adjudication will occur in a blinded, consistent, and unbiased 


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manner throughout the course of a study to determine whether the endpoints meet the protocol-specified 
criteria. 
The CEC will be comprised of 2 hepatologists, 2 cardiologists, 1 endocrinologist, and 3 histopathologists, all 
of whom will be independent of the participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability, as well as the PK profile, of elafibranor has been 
conducted through 12 completed and 5 ongoing clinical trials. A total of 659 volunteers were randomized in 
these studies performed in Phase I centers, including 561 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes, 6 with end stage renal disease and 20 with hepatic 
impairment (Child-Pugh class A, B or C) have been randomized to date in the completed trials. Elafibranor 
daily doses ranged between 5 mg and 360 mg, with a treatment duration up to 16 days. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders and NASH. To date, 5 Phase IIa studies have been completed in 
which 297 patients were randomized. A Phase IIb trial has been completed, and evaluated the efficacy and 
safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. A Phase 2 study 
(GFT505B-216-1) was also conducted in Primary Biliary Cholangitis (PBC) and included 45 patients with 
PBC and inadequate response to UDCA. This study evaluated the efficacy and safety of elafibranor at doses 
of 80 mg and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor daily doses 
ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months. 
Of the 63 Treatment emergent SAEs that have been reported cumulatively in the completed clinical 
development program, 50 occurred with elafibranor and 13 with placebo. For all SAEs, the treatment code 
has been broken (end of study unblinding). 
Of the 50 SAEs that occurred with elafibranor, only 10 SAEs reported in 7 subjects were considered as 
having a reasonable possibility of relationship to elafibranor by the investigators (serious adverse reaction). 
They consisted of:  
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease treated with elafibranor 80 mg 
• 
Acute cholecystitis and pancreatitis that occurred in a patient on the second day of drug 
administration of elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 


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•
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor
120 mg.
•
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years (in
the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease).
•
Autoimmune hepatitis in a 56-year-old subject after 12 weeks of treatment of 120 mg elafibranor.
The subject received her last dose of investigational product before the event.
For atrial fibrillation, acute cholecystitis and pancreatitis, and Parkinson’s disease, after later investigations, 
given the medical history of the patients or the time of occurrence of the event, relationship to elafibranor 
was judged as “no reasonable possibility” by the Sponsor. 
All adverse reactions (adverse events reported by investigators as possibly related or related to study drug) 
reported in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at 
least 80 mg elafibranor per day are summarized in Table 3.  
Table 3: 
Overview of the common nonserious adverse reactions (>1% of patients 
treated with elafibranor) by system organ class (SOC) reported in completed elafibranor 
clinical studies with repeated administration of elafibranor (at least 14 days) from 80 mg/day 
up to 300 mg/day (MTD) 
System Organ Class 
Adverse Reaction 
Severity 
Number of cases 
(Frequency %) 
Gastrointestinal disorders 
Diarrhea 
Mild to moderate 17 (2.8%) 
Vomiting 
Mild to moderate 9 (1.5%) 
General disorders and administration 
site conditions 
Fatigue / Asthenia 
Mild to moderate 17 (2.8%) 
Investigations 
Hepatic enzymes increased 
(mainly transaminases) 
Mild to severe 
13 (2.1%) 
Blood creatine 
phosphokinase increased 
Mild to moderate 6 (1.0%) 
Musculoskeletal and connective tissue 
disorders 
Myalgia 
Mild to severe 
9 (1.5%) 
Metabolism and nutrition disorders 
Decreased appetite 
Mild to severe 
9 (1.5%) 
Nervous system disorders 
Dizziness 
Mild to moderate 6 (1.0%) 
Skin and subcutaneous tissue disorders 
Rash 
Mild to moderate 8 (1.3%) 
Renal and urinary disorders 
Renal failure/impairment 
Mild to moderate 7 (1.1%) 


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Among the non-serious adverse reactions, the most frequent were gastro-intestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue / asthenia. These are considered common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly AT), CPK elevation, or increase of creatinine (reported 
by investigators as renal failure and/or impairment due to the calculation of creatinine clearance by MDRD 
based on creatinine). Myalgia, decrease of appetite dizziness and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARα agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that investigators review these lab results in 
the course of clinical trials. 
Other known effects of PPARα agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014)34. 
As such, all clinical trials with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, with highly effective contraceptive measures throughout the study. It is recommended to 
maintain the contraception up to 1 month after end of treatment. Pregnancy tests should be repeated as 
stated in each study protocol.  
6.6.2. 
Safety data conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders and asthenia / fatigue are 
considered common non-serious adverse reactions reasonably associated with elafibranor. Most of them 
are of mild to moderate intensity. Laboratory increases in serum creatinine or CPK should be monitored 
throughout clinical trials as this has been observed in Phase II trials to date, and is a known PPARα agonist 
effect. Elevation of AT will be monitored as well as DILI. In the absence of extensive human pregnancy 
data, highly effective contraception should be maintained for women of childbearing potential participating 
in clinical trials with elafibranor treatment, up to 1 month after end of study treatment. 


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6.6.3. 
Benefit/risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 
objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Furthermore, the Phase IIa trial in PBC subjects who had an inadequate response to UDCA demonstrated 
similar improvement in GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP levels 
was observed, resulting in significant treatment effects versus placebo on the primary endpoint, whilst also 
meeting the composite endpoint used for drug registration (i.e. serum ALP <1.67 x ULN, an ALP decrease 
>15% and total bilirubin <ULN). 
Moreover, these studies have highlighted the good safety profile of elafibranor and no major safety 
concerns have been raised. 
Despite this favorable benefit-risk profile, an independent DSMB is to be established in order to review the 
safety of the treatment during the trial in an unblinded manner, to protect patient welfare and preserve 
study integrity. The safety assessments will be performed on a regular basis, every 6 months after 
Randomization of the first patient. The DSMB will consist of 5 experienced physicians (1 endocrinologist, 
1 cardiologist, 1 hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all independent of the 
participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression, mainly through noninvasive measures 
including FibroScan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor 
(propanoic 
acid, 
2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] 
phenoxy]-2-methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with 
no printed inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(February 2010) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 
packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: Product carton and wallet labeling 
. 


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7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Upon screening of the first patient, the IXRS system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 9 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the final database lock and the Sponsor authorization to unblind the trial. 
7.5. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.6. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS to determine the supply of study drugs sent to each 
site. Initial site shipments will be shipped at a static value defined in the supply strategy. Following 
randomization of a patient IXRS will project for the amount of study drug required for future visits and 
ensure the study drug is at site for the visits occurring. The IXRS will continue to project study drug 
requirements per patient until an event occurs which stops the projections for that patient. 


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The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the LTTP. An e-mail, confirming the registration, will be sent to the Investigator 
and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the LTTP. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the LTTP, which correspond 
to the number of tablets provided to the patient at each visit. 
7.7. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening Visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IXRS (24-hour & 7-day access) and entering their identification number 
and access code. A back-up phone Interactive Response Technology (IRT) module will also be available 
should the site be unable to access the internet. The IXRS will verify the authorization to unblind the 
entered treatment carton and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 
The reason for unblinding should be clearly and fully documented by the Investigator. 


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7.10. STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused cartons and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupted, whatever the cause, duration and reason of the interruption should be 
documented. 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will acknowledge receipt for each study treatment on the day of receipt. A 
drug accountability record should be maintained by the person responsible for dispensing the trial 
medication to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for treatment cartons 
destroyed recording: 
•
Treatment carton (kit) number (see APPENDIX V: Product carton and wallet labeling
•
Quantity destroyed
•
Method of destruction
•
Person who disposed the drug.
7.12. OTHER MEDICATION
7.12.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible (see table II in 
APPENDIX III: Permitted/non-permitted medication). In the event that it becomes necessary during the 
study, this should be recorded by the Investigator in the eCRF (including concomitant medications taken 
within 6 months prior to Screening) and information should be communicated to the Medical Monitor in 
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order to evaluate the risk of DDIs. This includes drugs used on a chronic as well as on an “as needed” 
basis. 
7.12.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/non-permitted medication): 
•
Thiazoledinediones (glitazones [pioglitazone & rosiglitazone])
•
Fibrates
•
Corticosteroids (parenteral & oral chronic administration only)
•
Amiodarone
•
Tamoxifen
•
Methotrexate
•
Indomethacin.
The following medications are not allowed to be initiated prior to diagnostic liver biopsy and up to 
72 weeks of treatment (see APPENDIX III: Permitted/non-permitted medication): 
•
GLP-1 agonist
•
SGLT2 inhibitors.
If it is identified that these non-permitted drugs have been administered to a patient within the excluded 
timeframes, the site will discuss the continuation of the patient with the Medical Monitors of the study. 
7.12.3. 
Permitted medication under condition 
The following medications are permitted under the condition of steady dosage prior to Screening (dose 
changes 
are 
allowed 
after 
Randomization 
if 
judged 
necessary 
by 
the 
physician): 
(see APPENDIX III: Permitted/non-permitted medication)): 
•
Statins, ezetimibe, and other nonfibrate lipid lowering medications, provided the dosage is kept
stable for at least 2 months prior to Screening.
The following medications are permitted under the condition of stable dose from at least 6 months prior to 
diagnostic liver biopsy (dose changes should be avoided up to EOT): 
•
Vitamin E >400 IU/day
•
PUFAs >2 g/day
•
UDCA
The following medications are permitted under the condition of no qualitative change (i.e., implementation 
of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy and up to Randomization: 


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• 
Insulin 
• 
Sulfonylureas 
• 
Metformin 
• 
Gliptins 
• 
SGLT2-inhibitors 
• 
GLP-1 agonists. 
Dose changes are allowed for these medications, except for GLP-1 agonists, which must be on stable dose 
in the 6 months prior to diagnostic liver biopsy and up to randomization. 
In addition, no initiation of SGLT2-inhibitors and GLP-1 agonists is allowed from at least 6 months prior to 
the diagnostic liver biopsy up to 72 week of treatment (V7). 
Patients on sulfonylureas and insulin are recommended to self-monitor blood glucose. 
7.12.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse events 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the last study visit. 
8.1.2. 
Adverse event of special interest (AESIs) 
AESIs are treatment emergent AEs corresponding to the conceptual definition of:  
 
• 
CPK elevations of severe intensity or leading to permanent study drug discontinuation 
• 
Muscle injury symptoms of severe intensity corresponding to:  
o 
Muscle pain or Myalgia 
o 
Muscle spasms or Tremor 
o 
Muscle weakness 
• 
Transaminases elevations from baseline of severe intensity or leading to permanent study drug 
discontinuation 
• 
Liver injury events of severe intensity corresponding to:  
o 
Hepatic impairment 
o 
Hepatic failure  
• 
Gastrointestinal symptoms of severe intensity corresponding to: 
o 
Abdominal pain 
o 
Constipation 
o 
Diarrhea 
o 
Nausea 
o 
Vomiting 
o 
Acute cholecystis 
o 
Acute pancreatitis 
• 
Fatigue and Asthenia of severe intensity 
• 
Serum creatinine elevations of severe intensity or leading to permanent study drug discontinuation 


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•
Renal injury events of moderate or severe intensity corresponding to:
o
Renal failure
o
Renal impairment
o
Renal colic
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are described 
in the Section 8.6.1. 
8.1.3. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is life-threatening (see Section 8.1.3.1)
•
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.3.2)
•
Results in persistent or significant disability/incapacity (see Section 8.1.3.3)
•
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous
abortions or elective abortions)
•
Is another medically important condition (see Section Erreur ! Source du renvoi introuvable.).
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. 
8.1.3.1. 
Life-threatening adverse events 
•
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at
risk of death at the time of the event; it does not refer to an event which hypothetically might
have caused death if it were more severe.
8.1.3.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. An overnight stay is defined by hospitalization of 24 hours. Visits to the emergency room will 
not be considered hospital admission. Pre-planned hospital stays or hospital stays for nonmedical social 
reasons will not be considered as hospitalization, for example: 
•
Hospitalization or prolongation of hospitalization is needed for a procedure required by the
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not
considered serious.
•
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the
study center (e.g., stent removal after surgery). This should be recorded in the study file.
•
Hospitalization for survey visits or annual physicals fall in the same category.


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• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.3.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.3.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.4. 
Clarification on serious adverse events: 
• 
Events that are identified as primary efficacy endpoints for the long-term evaluation should not be 
included as an AE. 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 


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8.1.5. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.6. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator’s Brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of a greater 
severity or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient 
• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 


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The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 
• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 


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Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until study end for each patient. Whenever possible, symptoms 
should be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, 
maximal intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
study end for each patient. 
8.3.2. 
Reporting a serious adverse event or an adverse event of special interest 
Serious AE reporting begins from signature of the patient ICF and ends at study end for each patient. 
AESI reporting starts from first study drug intake and ends at study end for each patient.  
Any SAE or AESI that is brought to the attention of the Investigator at any time after the reporting period 
and which is considered by him/her to be caused by the study drug within a reasonable possibility, should 
be reported. 
Any of the portal hypertension/cirrhosis related events described in Section 2.1.2 that are identified as 
potential primary efficacy endpoints for long-term evaluation will NOT be reported as SAEs unless it is 
determined by the adjudication committee that the event does not meet the predefined criteria for an 
endpoint. Events that are identified as potential primary efficacy endpoints for long-term evaluation that 
are not confirmed by adjudication will be reported as described with the start of the reporting time window 
being the time of negative adjudication decision. 
Investigators must notify, by e-mail or fax, the Sponsor designated representative 
 
 of all SAEs or AESI IMMEDIATELY (within 24 hours of the 
Investigator becoming aware of the event). 
 
 


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ANY SERIOUS ADVERSE EVENTS, OR ADVERSE EVENTS OF SPECIAL INTEREST WHETHER OR 
NOT RELATED TO THE STUDY DRUG, MUST BE REPORTED IMMEDIATELY (WITHIN 24 HOURS) 
TO 
 AT THE FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs or AESIs independent of the circumstances or suspected cause must be reported in ENGLISH on a 
SAE/AESI Form. The SAE/AESI Form should include a clearly written narrative describing signs, symptoms, 
intensity and treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae, in order to allow a complete medical assessment of the case and independent determination 
of the possible causality. 
The Investigator is also required to submit follow-up SAE/AESI reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE/AESI Form matches the 
information recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) according to the 
country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs (a serious ADR) 
• 
SUSARs (Suspected unexpected serious adverse reactions). 
Each SAE/AESI report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE/AESI report will be evaluated by 
the Sponsor and/or his designees who will assess the relationship to study procedure or study treatment 
and the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risk benefit analysis and is likely to have an impact on the 
patients who have participated in the trial will be reported by the Sponsor as soon as possible to the 
Competent Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until stabilization of the patient’s 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study (i.e. after EoT visit), notably for the potential related adverse events, and that 
additional investigations may be requested by the Sponsor. This information should be documented in the 
patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE, AESI or SAE as 
applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form, provided that pregnant female partners 
have signed an informed consent. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of first patient randomized and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment. Resolution of NASH is defined as the disappearance of ballooning (i.e., grade 0) 
and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with an overall 
pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH CRN 
fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the surrogate efficacy analysis when at least first 1023 randomized  F2 
and F3 patients complete the 72 week treatment period or discontinue early from the study treatment (see 
Section 9.8.1 for details). An additional exploratory analysis of this endpoint will take place at the time of 
the final analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
The long term endpoint of clinical outcomes is a composite endpoint composed of death due to any cause, 
histological liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 


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• 
MELD score ≥15 for patients with baseline MELD score ≤12 
• 
the onset of: 
o 
variceal bleed requiring hospitalization, 
o 
hepatic encephalopathy defined as West Haven/Conn score ≥2 and requiring 
hospitalization, 
o 
spontaneous bacterial peritonitis, 
o 
ascites requiring treatment. 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 96 months after the first patient is randomized. 
9.2.3. 
Key Secondary Endpoints 
The key secondary endpoints are: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: 
• 
Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, 
LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) 
These key secondary endpoints will be assessed at the time of the surrogate endpoint analysis (at least the 
first 1023 randomized patients with fibrosis stage F2 and F3) for the resolution of NASH without worsening 
of fibrosis endpoint. 
9.2.4. 
Other Secondary Endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the 
following endpoints: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (at the end of 
LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring (at the end of LTTP) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to 
NASH CRN scoring without worsening of NASH 
o 
percentage of patients with no worsening of Fibrosis and no worsening of NASH 
o 
percentage of patients with resolution of NASH and improvement of Fibrosis 


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o 
percentage of patients with at least a 1 point improvement in histological scores 
(NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], 
steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), 
or portal inflammation 
o 
percentage of patients with improvement of NAS of at least 2 points 
o 
percentage of patients with improvement of NAS of at least 2 points and with at least 
1 point improvement in hepatic ballooning 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and 
steatosis-activity-fibrosis (SAF) scoring 
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to NAS scoring and with at least 
1 point improvement in hepatic ballooning  
o 
percentage of patients with at least a 1 point improvement in disease activity score (sum 
of ballooning and lobular inflammation scores) according to steatosis-activity-fibrosis (SAF) 
scoring and with at least 1 point improvement in hepatic ballooning  
o 
percentage of patients with at least 2 points improvement in disease activity score 
according to NAS scoring and SAF scoring 
o 
changes in NAS, fibrosis (using NASH CRN and NAFLD Ishak scoring system), steatosis, 
hepatic ballooning, lobular inflammation, portal inflammation and SAF activity score 
o 
changes in area of fibrosis (normalized Collagen Proportional area in %) by morphometry. 
 
• 
To assess the following endpoints at Week 72 and at the end of the LTTP: 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in liver stiffness by Fibroscan measurement 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess the onset to: 
o 
histological liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events 
o 
cardiovascular events 
o 
liver-related death events. 


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9.2.5. 
Exploratory endpoints 
The exploratory endpoint is: 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all F2 and F3 patients who receive at least 1 dose of study drug. This set will be 
used to summarize safety. 
• 
Efficacy evaluable set (EES): All F2 and F3 patients in the ITT population who have taken at least 
one dose of study treatment and have a reliable liver biopsy at both baseline and at the end of the 
72 week treatment period. 
• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS.  
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients.  
• 
Full Safety Set (FSS): all r patients who receive at least 1 dose of study drug. 
Patients in the ITT, FITT, EES, PPS, and exploratory F1 cohorts (study population and efficacy data) will be 
analyzed based on randomized treatment. Patients in the SS, FSS, and exploratory F1 cohorts (safety data) 
will be analyzed based on actual treatment received. 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 


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using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. According to the method described in Ge et al. (2011)36, 
the statistical model will be used to estimate the difference (elafibranor/placebo) in rate of resolution of 
NASH without worsening of fibrosis and its 99% CI. The main confirmatory analysis will be performed 
when at least the first 1023 randomized F2/F3 patients have completed the 72 week treatment period or 
discontinued early from the study treatment. The main analysis will be based on the ITT. Supportive 
analysis will be based on the EES and PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Supplementary analyses using multiple imputations and a pattern 
mixture model will be performed, as well as sensitivity analysis using a Cochran-Mantel-Haenszel test. 
Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis is that there is no difference in the hazard ratio between the elafibranor and placebo 
treatment groups. The alternative hypothesis is that there is a difference in the hazard ratio between the 
elafibranor and placebo treatment groups. The null hypothesis will be tested at the two-sided 0.04 alpha 
level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, 
type 2 diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used 
to calculate the hazard ratio (elafibranor/placebo) and 96% confidence interval. This will be performed 
when at least 456 patients experience a clinical event/death. The time to clinical event/death will also be 
analyzed using an unadjusted Cox-proportional hazard’s model, log rank test and a nonparametric 
randomization based analysis of covariance method proposed by Saville and Koch.37  
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the ITT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS by NASH CRN scoring. The analysis will be performed at the time of the 


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surrogate endpoint analysis when at least the first 1023 randomized patients with fibrosis stage F2 and F3 
have completed the 72 week treatment period or discontinued early from the study treatment. The null 
hypothesis will be tested at the two-sided 0.01 alpha level. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant. A gatekeeping procedure will be constructed to control the overall Type I error rate for testing 
the key secondary efficacy endpoints at an overall two-sided alpha level of 0.01.  
The main analysis will be based on the IIT. Supportive analyses will be based on the EES and PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints such as time to first cardiovascular event/death will be analyzed using the Cox 
proportional hazard’s model in the same manner as time to clinical event/death. 
Continuous endpoints will be analyzed using a repeated measures Analysis of Covariance (ANCOVA) model 
with fixed terms for treatment, type 2 diabetes, gender, fibrosis stage, baseline NAS, and time-point and 
treatment by time-point interaction. A compound symmetry covariance matrix will be used for this analysis. 
The statistical model will be used to calculate the mean treatment difference and 95% confidence interval. 
If the data does not meet the required assumptions for parametric tests, the data will be analyzed using a 
nonparametric analysis of covariance method of Zink and Koch.41  
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Other) 
• 
Ethnicity (Hispanic, not Hispanic) 
• 
Age (<60, ≥60 years). 


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• 
PNPLA3 (absence or presence of risk allele G [i.e. CC vs GG/CG], and within the at risk group, 
homozygous vs. heterozygous for the risk allel G [i.e. CG vs GG]) 
• 
Patients under statins (yes/no), defined as patients who have duration of IP exposure greater or 
equal to 60 days, with extent of exposure to statin greater than or equal to 30 days before the visit 
7 biopsy date.  
Forest plots will be generated for each of these endpoints for patients in the ITT population.  
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort and the 
FITT. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary endpoints in this study is two-sided α=0.05. The alpha for the 
primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided 
α=0.04 for time to clinical event/death. 
The key secondary efficacy endpoints will be tested only if the primary surrogate endpoint is statistically 
significant at a two-sided 1% significance level. A gatekeeping procedure will be constructed to control the 
overall Type I error rate for testing the key secondary efficacy endpoints at an overall two-sided alpha level 
of 0.01. 
The gatekeeping procedure will be detailed in the SAP and set up using the general method for building 
multi-stage parallel gatekeeping procedures in multiplicity problems with several families of null hypotheses 
(Dmitrienko and Tamhane, 2011, 2013).38 39 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 


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• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group. 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of at least 1023 patients provides 90% power to show that 
elafibranor is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 
conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 


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The number of patients to be enrolled may be adjusted during the course of the study in a blinded manner 
to achieve the desired number of primary events.  This will be accomplished using standard event 
forecasting methods (Anisimov, 2011).40 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, AESI, clinical laboratory tests, vital signs, and ECGs) will be summarized by 
treatment group using descriptive statistics. The main summaries of safety will be based on the SS. 
Additional safety analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. AESIs, Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE and AESIs. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. 
9.8.1. 
Surrogate endpoint analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when at least the first 1023 
randomized F2 and F3 patients complete 72 weeks of treatment or discontinue early from the study 
treatment. The null hypothesis will be tested at the two-sided 0.01 alpha level. 
At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. A Data integrity 
plan will be set-up to detail the blinding/unblinding process and address how data will be published in view 
of marketing authorization and how integrity of the trial will be protected. 
 


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The DSMB will periodically review safety data from the study to ensure the well-being of study participants. 
One dedicated meeting will also be held upon availability of the surrogate endpoint analysis results.  
DSMB will be provided with data summaries that will include selected efficacy results so that the DSMB can 
assess the likely benefit-risk profile of elafibranor. These are not considered a formal interim analysis, and 
no type I error adjustments will be done for these reviews. Details will be in the DSMB Charter. 
9.9. 
INTERIM ANALYSIS 
An adaptive design interim analysis will be performed after 140 primary events (approx. 30% of the 
456 required events) have been accrued. The interim analysis will be performed by an unblinded team 
separate from the study team. The Data Safety Monitory Board (DSMB) will review the interim analysis 
results and provide final recommendations regarding trial termination due to futility and adjustment of the 
target number of primary events. Details will be in the DSMB Charter and SAP. 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE/AESI forms and SF-36 which will be collected via ePRO (which is then transferred to the electronic 
data capture). Patients will not be identified by name in the eCRF or on any study documents to be 
collected by the Sponsor (or designee) but will be identified by a patient number. 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 


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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I: World Medical Association Declaration of Helsinki) and that valid data 
are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs/AESIs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of mandatory and critical 
data and source document review of critical processes, and will be supported by formal remote site 
monitoring activities. Centralized monitoring activities will review study data to assess changes in individual 
site risk and to identify emerging trends, risks and issues across sites, countries, regions, and the global 
study. Further details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I: World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable regulatory 
authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel will adhere to all requirements for patient 
confidentiality, and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, other than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed 
1 year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the last observation for the last patient participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
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2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. 
Clin Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses 
in 
the 
murine 
liver 
induced 
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chemicals. 
Hepatology. 
2001;34: 288-297. 
6. Poniachik J, Santibanez C, Haim D, et al. Enhancement in liver nuclear factor-kb (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and 
fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. 
Epub 2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. 
Clin Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre 
D, 
Fromenty 
B, 
Mansouri 
A. 
Mitochondrial 
injury 
in 
steatohepatitis. 
Eur J Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al. Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G . Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH . Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. 
J Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. 
Clin Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy testing in clinical trials. Available at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
36. Ge, M., Durham, L. K., Meyer, R. D., Xie, W., & Thomas, N. (2011). Covariate-adjusted 
difference in proportions from clinical trials using logistic regression and weighted risk 
differences. Drug Information Journal, 45(4), 481-493. 
37. Saville RS and Koch G. Estimating Covariate-Adjusted Log Hazard Ratios in Randomized Clinical 
Trials Using Cox Proportional Hazards Models and Nonparametric Randomization Based 
Analysis of Covariance. Journal of Biopharmaceutical Statistics. 2013 23: 477-490. 
38. Dmitrienko, A., Tamhane, A.C. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011 30: 1473-1488. 
39. Dmitrienko, A., Tamhane, A.C.  General theory of mixture procedures for gatekeeping. 
Biometrical Journal. 2013 55: 402-419. 
40. Anisimov, V. Predictive event modelling in multicentre clinical trials with waiting time to 
response. Pharmaceutical Statistics. 2011; 10, 517-522. 
41. Zink RC and Koch G. NParCov3: A SAS/IML Macro for Nonparametric Randomization-Base 
Analysis of Covariance. Journal of Statistical Software. 2012 July 50:3. 
 
.  
 


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Appendices 


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APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
- 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1.1 Portugal 
DATE: 
July 25, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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AMENDMENT 1.1 – PORTUGAL: 25 JULY 2016 
Amendment 1.1 – Portugal addresses the grounds for non-acceptance from the Medical Products Agency 
dated 16 June 2016. 
Two revisions were made to protocol in the sections noted below. Added text is bolded; deleted text is 
struck through. 
Summary of the major change to the protocol: 
Section 
Updated Text 
6.6 Guidance 
for 
Investigators 
6.6.1 Summary of safety data (New subheading added above original text) 
Conclusion on the safety data 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as 
nausea, diarrhea, and vomiting, asthenia or fatigue, myalgia are considered common and 
expected adverse reactions reasonably associated with GFT505 elafibranor. Most of 
them are of mild to moderate intensity. As previously, laboratory increases of serum 
creatinine or CPK should be monitored throughout clinical trials as this has been observed 
in Phase 2 II trials, and is a known PPARalpha agonist effect. Elevation of transaminases 
will be monitored as well as drug-induced liver injury. In the absence of human 
pregnancy data, double contraception should be maintained for women of childbearing 
potential participating in clinical trials with GFT505 elafibranor treatment, up to 1 month 
after end of study treatment. 
6.6.2 Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that 
support the therapeutic potential of elafibranor in metabolic diseases including 
NASH. Moreover, the Phase IIb trial demonstrated the efficacy of elafibranor at 
the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, 
resolution of histological NASH without worsening of fibrosis, in patients with 
active disease (NAS ≥4). While the trial was short and not designed for 
antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg daily, 
improved fibrosis indirectly through the resolution of NASH. Importantly, 
elafibranor 120 mg concomitantly improved the cardiometabolic risk profile of 
the patients by decreasing plasma triglycerides, total and LDL-cholesterol, 
increasing HDL-Cholesterol, and improving inflammation, insulin resistance, 
and glucose homeostasis. Together these results position elafibranor as a drug 
candidate to treat NASH with the objective to block fibrosis evolution and 


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ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety 
concerns associated with elafibranor treatment, thus providing a favorable 
efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety 
Monitoring Board (DSMB) is established in order to review the safety of the 
treatment during the trial in an unblinded manner, to protect patient welfare 
and preserve study integrity. The safety assessments will be performed on a 
regular basis every 6 months after inclusion of the first patient. The DSMB 
consists of 4 experienced physicians (one endocrinologist, one cardiologist, one 
hepatologist, and one nephrologist) and one statistician, all independent of the 
participants in the study.  
In addition, throughout the study, patients will benefit from close safety 
monitoring including assessment of many safety parameters and follow-up of 
the disease progression mainly through noninvasive measures including 
fibroscan. 
10.1 CRF and 
source 
documents 
It is the Investigator’s obligation to ensure documentation of all relevant data in the 
patient’s medical file (medical history, concomitant diseases, patient identification 
number, date of informed consent, visit dates, administration of study medication, AEs 
[start and stop dates] and all concomitant medications [start and stop dates]). All data 
recorded in the eCRF will be documented by source data (e.g., but not limited to, 
doctors notes, X rays, hospital reports, or on any electronic device [ePRO]). 
If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any 
other kind of electronic devices) as part of regulated clinical trial activities, 
such systems must be compliant with all applicable laws and regulations 
governing use of electronic records and/or electronic signatures. Such systems 
may include, but are not limited to, electronic medical/health records, AE 
tracking/reporting, protocol-required assessments, and/or drug accountability 
records. 
 
 
Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 


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 
The version number and date were updated throughout the protocol 
 
Typographical and formatting errors were corrected throughout the protocol. 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Exploratory objectives 
 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 


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o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
 
Safety secondary objectives 
 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
 
NAS ≥4. 
 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT), obesity defined by a body mass index (BMI) 30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or homeostasis model assessment of insulin resistance 
(HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
 
674 patients in placebo group 
 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
 
Screening Period: Week-12 to Week -1 prior to Randomization. 
 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 


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3. Body Mass Index ≤45 kg/m². 
4. Females participating in the study must either not be of childbearing potential (hysterectomy, 
bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation 
of menses for at least 12 months due to ovarian failure) or using efficient double contraception: 
hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device, or other 
mechanical contraception method + condom or diaphragm or spermicide for the full duration of the 
study and for 1 month after the end of treatment. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic 
acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in antidiabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e., implementation of a new antidiabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfamides, or insulin. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients. 
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol Consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 


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o 
positive hepatitis C Virus RNA) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
25. Positive anti-human immunodeficiency virus antibody. 
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. International normalized ratio >1.4. 
29. platelet count <100,000/mm3. 
30. Serum creatinine levels >135 µmol/L (>1.53 mg/dL) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 
repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 


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Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
 
liver transplantation 
 
MELD score ≥15 
 
HCC 
 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 


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Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
 
Regulatory/ethics committee submission: January 2016 
 
Initiation visits: February 2016 – March 2017 
 
Recruitment period: February 2016 – December 2017 
 
FPFV: February 2016 
 
Interim analysis : August – October 2018 
 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction, and stroke events as 
defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 








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8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
10. ECG will be performed every 48 weeks starting at V9. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 






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= fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; 
NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing protein 3; PT  = 
prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = triglyceride; VLDL-C 
= very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:  
 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 1.1 – SWEDEN: 29 JUNE 2016 .......................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 12 
TABLE OF CONTENTS ......................................................................................................................... 27 
TABLE OF TABLES .............................................................................................................................. 33 
TABLE OF FIGURES ............................................................................................................................ 34 
LIST OF ABBREVIATIONS .................................................................................................................... 35 
1. 
INTRODUCTION ................................................................................................................... 38 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 38 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 38 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 40 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 41 
1.4.1. 
Pharmacology ........................................................................................................... 41 
1.4.2. 
Safety pharmacology ................................................................................................. 42 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 42 
1.4.4. 
Toxicology ................................................................................................................ 43 
1.5. 
CLINICAL STUDIES ............................................................................................................... 44 
1.5.1. 
Phase I program ........................................................................................................ 44 
1.5.2. 
Phase II program ...................................................................................................... 45 
1.6. 
CONCLUSION ....................................................................................................................... 48 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 48 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 49 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 49 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 49 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 50 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 50 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 51 
2. 
TRIAL OBJECTIVES ............................................................................................................... 53 
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 53 
2.1.1. 
Surrogate endpoint -Interim analysis .......................................................................... 53 
2.1.2. 
Long-term endpoint ................................................................................................... 53 


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2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ............................................................... 53 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 54 
2.4. 
EXPLORATORY OBJECTIVES.................................................................................................. 54 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .......................................................................... 55 
2.6. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 55 
3. 
TRIAL DESIGN ..................................................................................................................... 57 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 57 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 57 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 58 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 58 
3.5. 
STUDY PERIODS .................................................................................................................. 58 
3.6. 
SCREENING PERIOD ............................................................................................................. 58 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .............. 58 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 60 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 60 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 60 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 61 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 61 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 62 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 62 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ................................................ 63 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 63 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 64 
3.11. OPTIONAL VISITS ................................................................................................................ 66 
3.11.1. 
Retesting screening visits ........................................................................................... 66 
3.11.2. 
Unscheduled visits ..................................................................................................... 66 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 66 
4. 
PATIENT SELECTION ............................................................................................................ 67 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 67 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 68 
5. 
TRIAL PROCEDURES ............................................................................................................. 71 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 71 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 71 
5.1.2. 
Dietary and fluid restrictions ....................................................................................... 71 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 72 
5.2.1. 
Handling of patient withdrawal ................................................................................... 72 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 72 
5.2.3. 
Patient discontinuation from the Study ........................................................................ 73 
5.2.4. 
Patients lost to follow-Up ........................................................................................... 74 


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5.2.5. 
Replacement ............................................................................................................. 74 
5.2.6. 
Premature discontinuation of the study ....................................................................... 74 
6. 
ASSESSMENTS ..................................................................................................................... 75 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 75 
6.1.1. 
Histological assessments ............................................................................................ 75 
6.1.2. 
Biological assessments ............................................................................................... 76 
6.1.3. 
Constitution of biobank .............................................................................................. 77 
6.1.4. 
Pharmacokinetics evaluation ...................................................................................... 77 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 78 
6.2.1. 
Physical examination.................................................................................................. 78 
6.2.2. 
Vital signs ................................................................................................................. 78 
6.2.3. 
Electrocardiogram...................................................................................................... 79 
6.2.4. 
FibroScan .................................................................................................................. 79 
6.2.5. 
Quality of life questionnaire ........................................................................................ 80 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 80 
6.3.1. 
Creatine phosphokinase ............................................................................................. 80 
6.3.2. 
Liver function monitoring ........................................................................................... 80 
6.3.3. 
Threshold for diagnostic of cirrhosis ............................................................................ 82 
6.4. 
SAFETY DATA REVIEW ......................................................................................................... 82 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 82 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 83 
6.6.1. 
Summary of safety data ............................................................................................. 83 
6.6.2. 
Benefit / risk assessment ........................................................................................... 85 
7. 
TREATMENTS ....................................................................................................................... 87 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 87 
7.2. 
PACKAGING AND LABELING .................................................................................................. 87 
7.2.1. 
Packaging ................................................................................................................. 87 
7.2.2. 
Labeling .................................................................................................................... 87 
7.2.3. 
Dosage and administration of Elafibranor and placebo ................................................. 88 
7.2.4. 
Prior and concomitant medications ............................................................................. 88 
7.3. 
STORAGE CONDITIONS ........................................................................................................ 88 
7.4. 
DISPENSING OF TREATMENT ................................................................................................ 88 
7.5. 
TREATMENT REPLACEMENT .................................................................................................. 89 
7.6. 
PROCEDURE FOR BLINDING ................................................................................................. 89 
7.7. 
PROCEDURE FOR UNBLINDING ............................................................................................. 89 
7.8. 
STUDY DRUG COMPLIANCE .................................................................................................. 90 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 90 
7.10. OTHER MEDICATION ............................................................................................................ 90 


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7.10.1. 
Handling of concomitant medication ........................................................................... 90 
7.10.2. 
Non-permitted medication .......................................................................................... 91 
7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) ............................................................................................................... 91 
7.10.4. 
Permitted medication ................................................................................................. 92 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 93 
8.1. 
DEFINITIONS ....................................................................................................................... 93 
8.1.1. 
Adverse event ........................................................................................................... 93 
8.1.2. 
Serious adverse events .............................................................................................. 94 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 95 
8.1.4. 
Adverse drug reaction ................................................................................................ 96 
8.1.5. 
Unexpected adverse event ......................................................................................... 96 
8.2. 
ASSESSMENTS ..................................................................................................................... 96 
8.2.1. 
Intensity assessment ................................................................................................. 96 
8.2.2. 
Relation to the study treatment .................................................................................. 97 
8.2.3. 
Action taken and outcome .......................................................................................... 97 
8.3. 
REPORTING ......................................................................................................................... 98 
8.3.1. 
Reporting an adverse event ....................................................................................... 98 
8.3.2. 
Reporting a serious adverse event .............................................................................. 98 
8.3.3. 
Follow-up ................................................................................................................ 100 
8.4. 
POST STUDY REPORTING REQUIREMENTS .......................................................................... 100 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS .............................................................................. 100 
8.6. 
SPECIAL SITUATION REPORTS ........................................................................................... 101 
8.6.1. 
Pregnancy ............................................................................................................... 101 
8.6.2. 
Medication error ...................................................................................................... 101 
8.6.3. 
Misuse .................................................................................................................... 101 
8.6.4. 
Overdose ................................................................................................................ 102 
8.6.5. 
Abuse ..................................................................................................................... 102 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ..................................................................... 103 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ............................................................... 103 
9.2. 
ENDPOINTS ....................................................................................................................... 103 
9.2.1. 
Surrogate endpoint - resolution of NASH ................................................................... 103 
9.2.2. 
Long-term endpoint – time to clinical event/death ..................................................... 103 
9.2.3. 
Key secondary endpoint ........................................................................................... 104 
9.2.4. 
Other secondary endpoints ...................................................................................... 104 
9.2.5. 
Exploratory endpoints .............................................................................................. 105 
9.3. 
ANALYSIS SETS .................................................................................................................. 105 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS.................................................................................... 106 


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9.4.1. 
Resolution of NASH.................................................................................................. 106 
9.4.2. 
Long-term endpoints ............................................................................................... 106 
9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................... 107 
9.5.1. 
Key secondary endpoint ........................................................................................... 107 
9.5.2. 
Other secondary endpoints ...................................................................................... 107 
9.5.3. 
Subgroup analyses .................................................................................................. 108 
9.5.4. 
Exploratory analyses ................................................................................................ 108 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 108 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 109 
9.7.1. 
Resolution of NASH.................................................................................................. 109 
9.7.2. 
Time to clinical event/death ..................................................................................... 109 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 110 
9.8.1. 
Interim analysis ....................................................................................................... 110 
9.9. 
BLINDED REASSESSMENT ................................................................................................... 111 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 112 
10.1. CRF AND SOURCE DOCUMENTS .......................................................................................... 112 
10.2. RETENTION OF RECORDS ................................................................................................... 113 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 114 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 114 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 115 
11.3. QUALITY ASSURANCE ......................................................................................................... 115 
12. 
ETHICS AND REGULATORY ................................................................................................. 116 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 116 
12.2. COMPETENT AUTHORITY ................................................................................................... 117 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 117 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 117 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 118 
13. 
FINANCING AND INSURANCE .............................................................................................. 119 
13.1. FINANCIAL ISSUES ............................................................................................................. 119 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 119 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 120 
14.1. STUDY REPORT .................................................................................................................. 120 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 120 
15. 
REFERENCES LIST .............................................................................................................. 122 
APPENDICES .................................................................................................................................... 125 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 126 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 135 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 136 


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APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 138 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 139 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 19 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 23 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 80 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 84 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
26 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 


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HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNF 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 


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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)/ modulators with preferential activity on PPAR over 
PPAR (about fivefold more potent on human PPAR [hPPAR] than on hPPAR). The PPAR properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPAR 
response) and human hepatocytes (a mixed PPAR/ response). 
The PPAR receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPAR activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPAR compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPAR appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPAR agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPAR ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNF, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPAR knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNF, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPAR knockouts. 
Finally, in a short clinical trial, a pure PPAR agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing GT.16 


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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPAR 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPAR encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPAR and PPAR in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPAR-dependent and PPAR-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPAR reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPAR -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPAR 


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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPAR reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 


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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPAR-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPAR-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 


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1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor  has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 


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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 


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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 


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(-20% to -35%), reduction in low-density lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 


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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), Phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 


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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 


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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 


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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 


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 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
 
SAE, AE, physical examination, vital signs, medical history, ECG 
 
hematological parameters 
 
liver function parameters 
 
renal function parameters (including urinalysis) 


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 
cardiac function parameters 
 
metabolic parameters 
 
other biochemical safety markers. 
 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long-term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
 
Elafibranor 120 mg 
 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 


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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
 
Signature of informed consent witnessed by the Investigator or designated person. 
 
Patient number allocation via IXRS. 
 
Check medical history/demographics. 
 
Check inclusion/exclusion criteria (described in Section 4). 
 
Physical examination (described in Section 6.2.1). 


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 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
 
Record vital signs (described in Section 6.2.2). 
 
Record height, weight, and waist circumference. 
 
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10 
and APPENDIX III: Permitted/Non-permitted medication) 
 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1. 
 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
 
Blood samples (described in Table 2). 
 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
 
Urinalysis dipstick. 
 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 31, 
and 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 2 digits corresponding to the site number (this number will be predefined), 
 Last 2 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
 
Check inclusion/exclusion criteria (detailed in Section 4). 
 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 


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 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference (V1, V3, V5, and V7, only). 
 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 


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The following procedures will be performed at each visit from V8 to Vn: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
 
FibroScan (described in Section 6.2.4) 
 
Drug accountability 
 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety and IP compliance control. If any information during this phone contact requires a visit, 
the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS 
registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 


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All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, and Figure 1. 
The following procedures will be performed at the EOT Visit: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (described in Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (described in Section 6.2.3) 
 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 


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including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
 
IXRS registration. 
 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
 
Reporting of any change in diet and life style factors 
 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 


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3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization. 
 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1). 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the Screening Period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral 
oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses 
for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal 
contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical 
contraception method + condom or diaphragm or spermicide for the full duration of the study and for 
1 month after the end of treatment. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 
treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or 
ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy.  
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions: 
 
No change in dose for patients treated by GLP-1 agonists 


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 
No qualitative change (i.e., implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfamides, or insulin. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients. 
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
 
Positive hepatitis B surface antigen (HBsAg) 
 
HCV RNA 
 
Suspicion of drug-induced liver disease 
 
Alcoholic liver disease 
 
Autoimmune hepatitis 


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 
Wilson’s disease hemochromatosis 
 
Primary biliary cirrhosis, primary sclerosing cholangitis 
 
Genetic hemochromatosis 
 
Known or suspected HCC 
 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
25. Positive anti-human immunodeficiency virus (HIV) antibody. 


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26. AST and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. INR >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, and 
Figure 1) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 


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 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 


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 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
 
Non-compliance with the study treatment 
 
Uncooperative patient 
 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 


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5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 


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6. 
ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
 
Needle core biopsy 
 
Biopsy obtained with a 16 or lower gage needle 
 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 


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The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
 
HIV ab I/II 
 
HBsAg 
 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
 
To discover or validate biomarkers in NASH and related diseases. 
 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 


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Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 


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6.2.2.1. 
Important points for clinical blood pressure measurement: 
 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT Visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 


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Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e., ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT Visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 
must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 


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For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 


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 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the 
Long-term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or ascites, 
then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will have to be 
adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e., cardiovascular death, nonfatal myocardial, infarction, and stroke 
events as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, 
consistent, and unbiased manner throughout the course of a study to determine whether the endpoints 
meet the protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 


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6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. 
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 


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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by Investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that Investigators review these lab results in 
the course of clinical trials. 


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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014). 
As such, all clinical trials with elafibranor including women of childbearing potential request a negative 
pregnancy test before Randomization, with effective contraceptive measures throughout the study. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods 
during clinical trials should be avoided, and they should be accompanied by barrier methods. 
Conclusion on the safety data 
Based on the cumulative experience gathered to date, gastrointestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with elafibranor. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in Phase II trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
elafibranor treatment, up to 1 month after end of study treatment. 
6.6.2. 
Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-Cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 


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objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis every 6 months after inclusion of the first patient. The DSMB consists of 4 experienced physicians 
(one endocrinologist, one cardiologist, one hepatologist, and one nephrologist) and one statistician, all 
independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression mainly through noninvasive measures 
including fibroscan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 


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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 


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value defined in the supply strategy. Following Randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 


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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
 
Blister identification 
 
Quantity destroyed 
 
Method of destruction 
 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 


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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
 
Glitazones (pioglitazone & rosiglitazone) 
 
Fibrates 
 
Corticosteroids (parenteral & oral chronic administration only) 
 
Amiodarone 
 
Tamoxifen 
 
Methotrexate 
 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 


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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfamides 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfamides and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
 
Test result is associated with accompanying symptoms 
 
Test result requires additional diagnostic testing or medical/surgical intervention 
 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
 
Overdose without clinical sequelae 


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 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
 
Uncomplicated pregnancy 
 
An induced elective abortion to terminate a pregnancy without medical reason 
 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (see Section 8.1.2.1) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 


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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 
Hospitalization for survey visits or annual physicals fall in the same category. 
 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias or convulsions that do not result in hospitalization 
 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
 
As an outcome event, progression to cirrhosis should not be included as AE. 
 
Death is an outcome of an AE, not an AE in itself. 


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 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 


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 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
 
Dose not changed – in case no action is taken regarding the study drug 


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 
Unknown 
 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
 
Recovered/resolved 
 
Recovering/resolving 
 
Not recovered/not resolved 
 
Recovered/resolved with sequelae 
 
Fatal 
 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
the last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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 
SAEs (including events related to study procedures) 
 
SADRs 
 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 


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 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key secondary endpoint 
The key secondary endpoint is: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other secondary endpoints 
The other secondary endpoints are: 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 


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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 


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 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS. 
 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
 
Full Intent-To-Treat Set (FITT): all randomized patients. 
 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS,and exploratory F1 cohorts (study population and efficacy data) will analyzed 
based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 


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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 


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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
Presence of type 2 diabetes (yes, no) 
 
Gender (male, female) 
 
Fibrosis (F2, F3) 
 
Geographic region (North America, Europe, South America, Rest of World) 
 
Race (Caucasian, Hispanic, Other) 
 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided =0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided =0.01 for resolution of NASH and two-sided =0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided =0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided =0.01 for resolution of NASH and 
two-sided =0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided =0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
 
=0.01 two-sided 
 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
 
Pooled variance 
 
Randomization ratio of 2:1 (elafibranor: placebo) 
 
8% response in the control group 
 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
 
72 month maximum follow-up 
 
=0.04 two-sided 
 
Annual event rate of 7% for the placebo group 
 
Hazard ratio of 0.75 in favor of the elafibranor group 
 
4% annual drop-out rate over 72 months 
 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 


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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e., 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 


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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11.  
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 


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The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical Investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santiban˜ez C, Haim D, et al. Enhancement in liver nuclear factor-KB (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and 
fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. 
Epub 2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. 
Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al.,Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, 
and 
increases 
fatty 
acid 
oxidation 
in 
moderately 
obese 
men. 
Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell. Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell. Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 


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Appendices 


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APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1.2 Portugal 
DATE: 
September 16, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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AMENDMENT 1.2 – PORTUGAL: 16 SEPTEMBER 2016 
Amendment 1.2 – Portugal addresses the comment received from the National Ethics Committee for 
Clinical Research dated 01 September 2016 regarding liver biopsy (comment #2) and comments received 
from the National Authority of Medicines and Health Products dated 24 August 2016 regarding methods of 
contraception. 
Two revisions were made to protocol in the sections noted below. Added text is bolded; deleted text is 
struck through.  
Summary of the major change to the protocol: 
Section 
Updated Text 
4.1 Inclusion 
criteria 
4. Females participating in the study must either not be of childbearing potential 
(hysterectomy, bilateral oophorectomy, medically documented ovarian failure, 
or >50 years of age with cessation of menses for at least 12 months due to 
ovarian 
failure) 
or 
using 
efficient 
double 
contraception: 
hormonal 
contraception (including patch, contraceptive ring, etc), intra uterine device, 
or other mechanical contraception method + condom or diaphragm or 
spermicide for the full duration of the study and for 1 month after the end of 
treatment. 
 
4. Females participating in this study must be of nonchildbearing 
potential or using highly efficient contraception for the full duration 
of the study and for 1 month after the end of treatment, as 
described below:  
 
Cessation of menses for at least 12 months due to ovarian 
failure 
 
Surgical 
sterilization 
such 
as 
bilateral 
oophorectomy, 
hysterectomy, or medically documented ovarian failure 
 
If requested by local IRB regulations and/or National laws, 
sexual 
abstinence 
may 
be 
considered 
adequate 
(the 
reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject) 
 
Using 
a 
highly 
effective 
nonhormonal 
method 
of 
contraception 
(bilateral 
tubal 
occlusion, 
vasectomized 
partner or intra-uterine device) 
 
Double contraception with barrier AND highly effective 
hormonal method of contraception (oral, intravaginal, or 


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transdermal combined estrogen and progestogen hormonal 
contraception associated with inhibition of ovulation, oral, 
injectable 
or 
implantable 
progestogen-only 
hormonal 
contraception associated with inhibition of ovulation or 
intrauterine 
hormone-releasing 
system). 
The 
hormonal 
contraception must be started at least one month prior to 
randomization. 
6.1.1.1 
Recommendations 
related to liver 
biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined 
indication for the biopsy, and the risks to the patient should not outweigh the 
potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some 
form of imaging of the liver within the preceding weeks. This will allow the detection 
of abnormal anatomy in the area of the proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital 
standards before the date of liver biopsy. Local guidelines and thresholds for 
hemostatic parameters should be used as they are in everyday clinical practice. 
Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing 
percutaneous liver biopsy in a patient that has stopped taking any antiaggregant 
therapy for >5 days. If these conditions are not all respected, a safer option would be 
to perform the liver biopsy by transjugular route, when available.  
Sedation is recommended to be given for percutaneous liver biopsy, and should be 
given with caution in liver disease. 
The recommended biopsy procedure to be applied is: 
 
Needle core biopsy 
 
Biopsy obtained with a 16 or lower gage needle 
 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for 
inclusion, a left lobe biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital 
at least for 6 hours after the procedure. 
The biopsies will be sent to the central laboratory and then to a central reader who 
will read the biopsies to determine the eligibility to the study according the fibrosis 
stage and consistency with NASH diagnosis. Biopsy slides will be blinded for patient 


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and visit identification prior to central reading. 
In cases where the liver biopsy fragment is too small or of bad quality, 
thereby precluding adequate reading, other available slides or new slides to 
be prepared from an available block of tissue may be requested from the 
site. 
 


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AMENDMENT 1.1 – PORTUGAL: 25 JULY 2016 
Amendment 1.1 – Portugal addresses the grounds for non-acceptance from the Medical Products Agency 
dated 16 June 2016. 
Two revisions were made to protocol in the sections noted below. Added text is bolded; deleted text is 
struck through. 
Summary of the major change to the protocol: 
Section 
Updated Text 
6.6 Guidance 
for 
Investigators 
6.6.1 Summary of safety data (New subheading added above original text) 
Conclusion on the safety data 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as 
nausea, diarrhea, and vomiting, asthenia or fatigue, myalgia are considered common and 
expected adverse reactions reasonably associated with GFT505 elafibranor. Most of 
them are of mild to moderate intensity. As previously, laboratory increases of serum 
creatinine or CPK should be monitored throughout clinical trials as this has been observed 
in Phase 2 II trials, and is a known PPARalpha agonist effect. Elevation of transaminases 
will be monitored as well as drug-induced liver injury. In the absence of human 
pregnancy data, double contraception should be maintained for women of childbearing 
potential participating in clinical trials with GFT505 elafibranor treatment, up to 1 month 
after end of study treatment. 
6.6.2 Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that 
support the therapeutic potential of elafibranor in metabolic diseases including 
NASH. Moreover, the Phase IIb trial demonstrated the efficacy of elafibranor at 
the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, 
resolution of histological NASH without worsening of fibrosis, in patients with 
active disease (NAS ≥4). While the trial was short and not designed for 
antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg daily, 
improved fibrosis indirectly through the resolution of NASH. Importantly, 
elafibranor 120 mg concomitantly improved the cardiometabolic risk profile of 
the patients by decreasing plasma triglycerides, total and LDL-cholesterol, 
increasing HDL-Cholesterol, and improving inflammation, insulin resistance, 
and glucose homeostasis. Together these results position elafibranor as a drug 
candidate to treat NASH with the objective to block fibrosis evolution and 


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ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety 
concerns associated with elafibranor treatment, thus providing a favorable 
efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety 
Monitoring Board (DSMB) is established in order to review the safety of the 
treatment during the trial in an unblinded manner, to protect patient welfare 
and preserve study integrity. The safety assessments will be performed on a 
regular basis every 6 months after inclusion of the first patient. The DSMB 
consists of 4 experienced physicians (one endocrinologist, one cardiologist, one 
hepatologist, and one nephrologist) and one statistician, all independent of the 
participants in the study.  
In addition, throughout the study, patients will benefit from close safety 
monitoring including assessment of many safety parameters and follow-up of 
the disease progression mainly through noninvasive measures including 
fibroscan. 
10.1 CRF and 
source 
documents 
It is the Investigator’s obligation to ensure documentation of all relevant data in the 
patient’s medical file (medical history, concomitant diseases, patient identification 
number, date of informed consent, visit dates, administration of study medication, AEs 
[start and stop dates] and all concomitant medications [start and stop dates]). All data 
recorded in the eCRF will be documented by source data (e.g., but not limited to, 
doctors notes, X rays, hospital reports, or on any electronic device [ePRO]). 
If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any 
other kind of electronic devices) as part of regulated clinical trial activities, 
such systems must be compliant with all applicable laws and regulations 
governing use of electronic records and/or electronic signatures. Such systems 
may include, but are not limited to, electronic medical/health records, AE 
tracking/reporting, protocol-required assessments, and/or drug accountability 
records. 
 
Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 
 
The version number and date were updated throughout the protocol 
 
Typographical and formatting errors were corrected throughout the protocol. 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Exploratory objectives 
 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 


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o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
 
Safety secondary objectives 
 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
 
NAS ≥4. 
 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT), obesity defined by a body mass index (BMI) 30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or homeostasis model assessment of insulin resistance 
(HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
 
674 patients in placebo group 
 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
 
Screening Period: Week-12 to Week -1 prior to Randomization. 
 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 


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3. Body Mass Index ≤45 kg/m². 
4. Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
 
Cessation of menses for at least 12 months due to ovarian failure  
 
Surgical sterilization such as bilateral oophorectomy, hysterectomy, or medically documented 
ovarian failure 
 
If requested by local IRB regulations and/or National laws, sexual abstinence may be 
considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the subject) 
 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner or intra-uterine device) 
 
Double contraception with barrier AND highly effective hormonal method of contraception (oral, 
intravaginal, or transdermal combined estrogen and progestogen hormonal contraception 
associated with inhibition of ovulation, oral, injectable, or implantable progestogen-only 
hormonal 
contraception 
associated 
with 
inhibition 
of 
ovulation 
or 
intrauterine 
hormone-releasing system). The hormonal contraception must be started at least one month 
prior to randomization. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic 
acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in antidiabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e., implementation of a new antidiabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfamides, or insulin. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients. 
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 


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are excluded. 
10. Current or recent history (<5 years) of significant alcohol Consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus RNA) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
25. Positive anti-human immunodeficiency virus antibody. 
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. International normalized ratio >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 µmol/L (>1.53 mg/dL) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 


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repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
 
liver transplantation 
 
MELD score ≥15 
 
HCC 
 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 


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 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
 
Regulatory/ethics committee submission: January 2016 
 
Initiation visits: February 2016 – March 2017 
 
Recruitment period: February 2016 – December 2017 
 
FPFV: February 2016 
 
Interim analysis : August – October 2018 
 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction, and stroke events as 
defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 








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8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
10. ECG will be performed every 48 weeks starting at V9. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 






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= fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; 
NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing protein 3; PT  = 
prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = triglyceride; VLDL-C 
= very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:  
 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 1.2 – PORTUGAL: 16 SEPTEMBER 2016 ............................................................................. 9 
AMENDMENT 1.1 – PORTUGAL: 25 JULY 2016 ..................................................................................... 12 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 14 
TABLE OF CONTENTS ......................................................................................................................... 29 
TABLE OF TABLES .............................................................................................................................. 35 
TABLE OF FIGURES ............................................................................................................................ 36 
LIST OF ABBREVIATIONS .................................................................................................................... 37 
1. 
INTRODUCTION ................................................................................................................... 40 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 40 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 40 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 42 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 43 
1.4.1. 
Pharmacology ........................................................................................................... 43 
1.4.2. 
Safety pharmacology ................................................................................................. 44 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 44 
1.4.4. 
Toxicology ................................................................................................................ 45 
1.5. 
CLINICAL STUDIES ............................................................................................................... 46 
1.5.1. 
Phase I program ........................................................................................................ 46 
1.5.2. 
Phase II program ...................................................................................................... 47 
1.6. 
CONCLUSION ....................................................................................................................... 50 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 50 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 51 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 51 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 51 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 52 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 52 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 53 
2. 
TRIAL OBJECTIVES ............................................................................................................... 55 
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 55 
2.1.1. 
Surrogate endpoint -Interim analysis .......................................................................... 55 


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2.1.2. 
Long-term endpoint ................................................................................................... 55 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ............................................................... 55 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 56 
2.4. 
EXPLORATORY OBJECTIVES.................................................................................................. 56 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .......................................................................... 57 
2.6. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 57 
3. 
TRIAL DESIGN ..................................................................................................................... 59 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 59 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 59 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 60 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 60 
3.5. 
STUDY PERIODS .................................................................................................................. 60 
3.6. 
SCREENING PERIOD ............................................................................................................. 60 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .............. 60 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 62 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 62 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 62 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 63 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 63 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 64 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 64 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ................................................ 65 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 65 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 66 
3.11. OPTIONAL VISITS ................................................................................................................ 68 
3.11.1. 
Retesting screening visits ........................................................................................... 68 
3.11.2. 
Unscheduled visits ..................................................................................................... 68 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 68 
4. 
PATIENT SELECTION ............................................................................................................ 69 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 69 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 70 
5. 
TRIAL PROCEDURES ............................................................................................................. 73 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 73 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 73 
5.1.2. 
Dietary and fluid restrictions ....................................................................................... 73 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 74 
5.2.1. 
Handling of patient withdrawal ................................................................................... 74 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 74 
5.2.3. 
Patient discontinuation from the Study ........................................................................ 75 


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5.2.4. 
Patients lost to follow-Up ........................................................................................... 76 
5.2.5. 
Replacement ............................................................................................................. 76 
5.2.6. 
Premature discontinuation of the study ....................................................................... 76 
6. 
ASSESSMENTS ..................................................................................................................... 77 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 77 
6.1.1. 
Histological assessments ............................................................................................ 77 
6.1.2. 
Biological assessments ............................................................................................... 78 
6.1.3. 
Constitution of biobank .............................................................................................. 79 
6.1.4. 
Pharmacokinetics evaluation ...................................................................................... 80 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 81 
6.2.1. 
Physical examination.................................................................................................. 81 
6.2.2. 
Vital signs ................................................................................................................. 81 
6.2.3. 
Electrocardiogram...................................................................................................... 81 
6.2.4. 
FibroScan .................................................................................................................. 82 
6.2.5. 
Quality of life questionnaire ........................................................................................ 82 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 82 
6.3.1. 
Creatine phosphokinase ............................................................................................. 82 
6.3.2. 
Liver function monitoring ........................................................................................... 83 
6.3.3. 
Threshold for diagnostic of cirrhosis ............................................................................ 84 
6.4. 
SAFETY DATA REVIEW ......................................................................................................... 84 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 85 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 85 
6.6.1. 
Summary of safety data ............................................................................................. 85 
6.6.2. 
Benefit / risk assessment ........................................................................................... 88 
7. 
TREATMENTS ....................................................................................................................... 90 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 90 
7.2. 
PACKAGING AND LABELING .................................................................................................. 90 
7.2.1. 
Packaging ................................................................................................................. 90 
7.2.2. 
Labeling .................................................................................................................... 90 
7.2.3. 
Dosage and administration of Elafibranor and placebo ................................................. 91 
7.2.4. 
Prior and concomitant medications ............................................................................. 91 
7.3. 
STORAGE CONDITIONS ........................................................................................................ 91 
7.4. 
DISPENSING OF TREATMENT ................................................................................................ 91 
7.5. 
TREATMENT REPLACEMENT .................................................................................................. 92 
7.6. 
PROCEDURE FOR BLINDING ................................................................................................. 92 
7.7. 
PROCEDURE FOR UNBLINDING ............................................................................................. 92 
7.8. 
STUDY DRUG COMPLIANCE .................................................................................................. 93 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 93 


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7.10. OTHER MEDICATION ............................................................................................................ 93 
7.10.1. 
Handling of concomitant medication ........................................................................... 93 
7.10.2. 
Non-permitted medication .......................................................................................... 94 
7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) ............................................................................................................... 94 
7.10.4. 
Permitted medication ................................................................................................. 95 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 96 
8.1. 
DEFINITIONS ....................................................................................................................... 96 
8.1.1. 
Adverse event ........................................................................................................... 96 
8.1.2. 
Serious adverse events .............................................................................................. 97 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 98 
8.1.4. 
Adverse drug reaction ................................................................................................ 99 
8.1.5. 
Unexpected adverse event ......................................................................................... 99 
8.2. 
ASSESSMENTS ..................................................................................................................... 99 
8.2.1. 
Intensity assessment ................................................................................................. 99 
8.2.2. 
Relation to the study treatment ................................................................................ 100 
8.2.3. 
Action taken and outcome ........................................................................................ 100 
8.3. 
REPORTING ....................................................................................................................... 101 
8.3.1. 
Reporting an adverse event ..................................................................................... 101 
8.3.2. 
Reporting a serious adverse event ............................................................................ 101 
8.3.3. 
Follow-up ................................................................................................................ 103 
8.4. 
POST STUDY REPORTING REQUIREMENTS .......................................................................... 103 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS .............................................................................. 103 
8.6. 
SPECIAL SITUATION REPORTS ........................................................................................... 104 
8.6.1. 
Pregnancy ............................................................................................................... 104 
8.6.2. 
Medication error ...................................................................................................... 104 
8.6.3. 
Misuse .................................................................................................................... 104 
8.6.4. 
Overdose ................................................................................................................ 105 
8.6.5. 
Abuse ..................................................................................................................... 105 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ..................................................................... 106 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ............................................................... 106 
9.2. 
ENDPOINTS ....................................................................................................................... 106 
9.2.1. 
Surrogate endpoint - resolution of NASH ................................................................... 106 
9.2.2. 
Long-term endpoint – time to clinical event/death ..................................................... 106 
9.2.3. 
Key secondary endpoint ........................................................................................... 107 
9.2.4. 
Other secondary endpoints ...................................................................................... 107 
9.2.5. 
Exploratory endpoints .............................................................................................. 108 
9.3. 
ANALYSIS SETS .................................................................................................................. 108 


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9.4. 
ANALYSIS OF PRIMARY ENDPOINTS.................................................................................... 109 
9.4.1. 
Resolution of NASH.................................................................................................. 109 
9.4.2. 
Long-term endpoints ............................................................................................... 109 
9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................... 110 
9.5.1. 
Key secondary endpoint ........................................................................................... 110 
9.5.2. 
Other secondary endpoints ...................................................................................... 110 
9.5.3. 
Subgroup analyses .................................................................................................. 111 
9.5.4. 
Exploratory analyses ................................................................................................ 111 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 111 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 112 
9.7.1. 
Resolution of NASH.................................................................................................. 112 
9.7.2. 
Time to clinical event/death ..................................................................................... 112 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 113 
9.8.1. 
Interim analysis ....................................................................................................... 113 
9.9. 
BLINDED REASSESSMENT ................................................................................................... 114 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 115 
10.1. CRF AND SOURCE DOCUMENTS .......................................................................................... 115 
10.2. RETENTION OF RECORDS ................................................................................................... 115 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 117 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 117 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 118 
11.3. QUALITY ASSURANCE ......................................................................................................... 118 
12. 
ETHICS AND REGULATORY ................................................................................................. 119 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 119 
12.2. COMPETENT AUTHORITY ................................................................................................... 120 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 120 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 120 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 121 
13. 
FINANCING AND INSURANCE .............................................................................................. 122 
13.1. FINANCIAL ISSUES ............................................................................................................. 122 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 122 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 123 
14.1. STUDY REPORT .................................................................................................................. 123 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 123 
15. 
REFERENCES LIST .............................................................................................................. 125 
APPENDICES .................................................................................................................................... 128 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 129 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 138 


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APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 139 
APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 141 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 142 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 21 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 25 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 82 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 87 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
28 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 


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HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNF 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 


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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)/ modulators with preferential activity on PPAR over 
PPAR (about fivefold more potent on human PPAR [hPPAR] than on hPPAR). The PPAR properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPAR 
response) and human hepatocytes (a mixed PPAR/ response). 
The PPAR receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPAR activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPAR compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPAR appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPAR agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPAR ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNF, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPAR knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNF, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPAR knockouts. 
Finally, in a short clinical trial, a pure PPAR agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing GT.16 


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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPAR 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPAR encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPAR and PPAR in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPAR-dependent and PPAR-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPAR reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPAR -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPAR 


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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPAR reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 


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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPAR-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPAR-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 


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1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor  has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 


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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 


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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 


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(-20% to -35%), reduction in low-density lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 


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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), Phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 


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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 


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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 


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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 


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 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
 
SAE, AE, physical examination, vital signs, medical history, ECG 
 
hematological parameters 
 
liver function parameters 
 
renal function parameters (including urinalysis) 


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 
cardiac function parameters 
 
metabolic parameters 
 
other biochemical safety markers. 
 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long-term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
 
Elafibranor 120 mg 
 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 


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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
 
Signature of informed consent witnessed by the Investigator or designated person. 
 
Patient number allocation via IXRS. 
 
Check medical history/demographics. 
 
Check inclusion/exclusion criteria (described in Section 4). 
 
Physical examination (described in Section 6.2.1). 


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 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
 
Record vital signs (described in Section 6.2.2). 
 
Record height, weight, and waist circumference. 
 
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10 
and APPENDIX III: Permitted/Non-permitted medication) 
 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1. 
 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
 
Blood samples (described in Table 2). 
 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
 
Urinalysis dipstick. 
 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 31, 
and 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 2 digits corresponding to the site number (this number will be predefined), 
 Last 2 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
 
Check inclusion/exclusion criteria (detailed in Section 4). 
 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 


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 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference (V1, V3, V5, and V7, only). 
 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 


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The following procedures will be performed at each visit from V8 to Vn: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
 
FibroScan (described in Section 6.2.4) 
 
Drug accountability 
 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety and IP compliance control. If any information during this phone contact requires a visit, 
the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS 
registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 


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All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, and Figure 1. 
The following procedures will be performed at the EOT Visit: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (described in Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (described in Section 6.2.3) 
 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 


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including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
 
IXRS registration. 
 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
 
Reporting of any change in diet and life style factors 
 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 


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3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization. 
 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1). 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the Screening Period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in this study must be of nonchildbearing potential or using highly efficient 
contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below:  
 
Cessation of menses for at least 12 months due to ovarian failure,  
 
Surgical sterilization such as bilateral oophorectomy, hysterectomy, or medically documented 
ovarian failure 
 
If requested by local IRB regulations and/or National laws, sexual abstinence may be considered 
adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject) 
 
Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, 
vasectomized partner or intra-uterine device) 
 
Double contraception with barrier AND highly effective hormonal method of contraception (oral, 
intravaginal, or transdermal combined estrogen and progestogen hormonal contraception 
associated with inhibition of ovulation, oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation or intrauterine hormone-releasing system). 
The hormonal contraception must be started at least one month prior to randomization. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 


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treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or 
ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy.  
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions: 
 
No change in dose for patients treated by GLP-1 agonists 
 
No qualitative change (i.e., implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfamides, or insulin. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients. 
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 


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11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
 
Positive hepatitis B surface antigen (HBsAg) 
 
HCV RNA 
 
Suspicion of drug-induced liver disease 
 
Alcoholic liver disease 
 
Autoimmune hepatitis 
 
Wilson’s disease hemochromatosis 
 
Primary biliary cirrhosis, primary sclerosing cholangitis 
 
Genetic hemochromatosis 
 
Known or suspected HCC 
 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 


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22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
25. Positive anti-human immunodeficiency virus (HIV) antibody. 
26. AST and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. INR >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, and 
Figure 1) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 


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 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 


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 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
 
Non-compliance with the study treatment 
 
Uncooperative patient 
 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 


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5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 


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6. 
ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
 
Needle core biopsy 
 
Biopsy obtained with a 16 or lower gage needle 
 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
In cases where the liver biopsy fragment is too small or of bad quality, thereby precluding adequate 
reading, other available slides or new slides to be prepared from an available block of tissue may be 
requested from the site. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 


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Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 
The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
 
HIV ab I/II 
 
HBsAg 
 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
 
To discover or validate biomarkers in NASH and related diseases. 
 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 


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6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 
Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 


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6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 
6.2.2.1. 
Important points for clinical blood pressure measurement: 
 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT Visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 


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6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 
Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e., ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT Visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 


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must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 
For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 


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 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 
 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the 
Long-term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or ascites, 
then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will have to be 
adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 


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The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e., cardiovascular death, nonfatal myocardial, infarction, and stroke 
events as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, 
consistent, and unbiased manner throughout the course of a study to determine whether the endpoints 
meet the protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. 
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 


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 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 


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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by Investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that Investigators review these lab results in 
the course of clinical trials. 


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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014). 
As such, all clinical trials with elafibranor including women of childbearing potential request a negative 
pregnancy test before Randomization, with effective contraceptive measures throughout the study. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods 
during clinical trials should be avoided, and they should be accompanied by barrier methods. 
Conclusion on the safety data 
Based on the cumulative experience gathered to date, gastrointestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with elafibranor. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in Phase II trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
elafibranor treatment, up to 1 month after end of study treatment. 
6.6.2. 
Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-Cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 


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objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis every 6 months after inclusion of the first patient. The DSMB consists of 4 experienced physicians 
(one endocrinologist, one cardiologist, one hepatologist, and one nephrologist) and one statistician, all 
independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression mainly through noninvasive measures 
including fibroscan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 


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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 


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value defined in the supply strategy. Following Randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 


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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
 
Blister identification 
 
Quantity destroyed 
 
Method of destruction 
 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 


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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
 
Glitazones (pioglitazone & rosiglitazone) 
 
Fibrates 
 
Corticosteroids (parenteral & oral chronic administration only) 
 
Amiodarone 
 
Tamoxifen 
 
Methotrexate 
 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 


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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfamides 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfamides and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
 
Test result is associated with accompanying symptoms 
 
Test result requires additional diagnostic testing or medical/surgical intervention 
 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
 
Overdose without clinical sequelae 


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 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
 
Uncomplicated pregnancy 
 
An induced elective abortion to terminate a pregnancy without medical reason 
 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (see Section 8.1.2.1) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 


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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 
Hospitalization for survey visits or annual physicals fall in the same category. 
 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias or convulsions that do not result in hospitalization 
 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
 
As an outcome event, progression to cirrhosis should not be included as AE. 
 
Death is an outcome of an AE, not an AE in itself. 


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 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 


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 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
 
Dose not changed – in case no action is taken regarding the study drug 


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 
Unknown 
 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
 
Recovered/resolved 
 
Recovering/resolving 
 
Not recovered/not resolved 
 
Recovered/resolved with sequelae 
 
Fatal 
 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
the last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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 
SAEs (including events related to study procedures) 
 
SADRs 
 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 


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 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key secondary endpoint 
The key secondary endpoint is: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other secondary endpoints 
The other secondary endpoints are: 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 


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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 


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 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS. 
 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
 
Full Intent-To-Treat Set (FITT): all randomized patients. 
 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS,and exploratory F1 cohorts (study population and efficacy data) will analyzed 
based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 


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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 


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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
Presence of type 2 diabetes (yes, no) 
 
Gender (male, female) 
 
Fibrosis (F2, F3) 
 
Geographic region (North America, Europe, South America, Rest of World) 
 
Race (Caucasian, Hispanic, Other) 
 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided =0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided =0.01 for resolution of NASH and two-sided =0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided =0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided =0.01 for resolution of NASH and 
two-sided =0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided =0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
 
=0.01 two-sided 
 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
 
Pooled variance 
 
Randomization ratio of 2:1 (elafibranor: placebo) 
 
8% response in the control group 
 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
 
72 month maximum follow-up 
 
=0.04 two-sided 
 
Annual event rate of 7% for the placebo group 
 
Hazard ratio of 0.75 in favor of the elafibranor group 
 
4% annual drop-out rate over 72 months 
 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 


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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e., 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 


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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11.  
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 


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The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical Investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
1. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842-845. 
2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
Semin Liver Dis. 2008;28: 370-379. 
3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
2004;114:147-152. 
5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
288-297. 
6. Poniachik J, Santiban˜ez C, Haim D, et al. Enhancement in liver nuclear factor-KB (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and 
fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. 
Epub 2002 Oct 7. 
8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. 
10. Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J 
Gastroenterol Hepatol. 2004;16:1095-1105. 
11. Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and 
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. 
Hepatology. 
2001;34:1158–1163. 
12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409-2415. 
13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
14. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of 
nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al.,Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, 
and 
increases 
fatty 
acid 
oxidation 
in 
moderately 
obese 
men. 
Diabetes. 
2008;57(2):332-339. Epub 2007 Nov 16. 
17. Kang K, Reilly SM, Karabacak V, et al. Adipocyte-derived TH2 cytokines and myeloid PPAR 
delta regultate macrophage polarization and insulin sensitivity. Cell. Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell. Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis 
of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
and 
ability 
to 
predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 


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Appendices 


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APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1.1 Sweden 
DATE: 
June 29, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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AMENDMENT 1.1 – SWEDEN: 29 JUNE 2016 
Amendment 1.1 – Sweden addresses the grounds for non-acceptance from the Medical Products Agency 
dated 16 June 2016. 
Two revisions were made to protocol in the sections noted below. Added text is bolded; deleted text is 
struck through. 
Summary of the major change to the protocol: 
Section 
Updated Text 
6.6 Guidance 
for 
Investigators 
6.6.1 Summary of safety data (New subheading added above original text) 
Conclusion on the safety data 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as 
nausea, diarrhea, and vomiting, asthenia or fatigue, myalgia are considered common and 
expected adverse reactions reasonably associated with GFT505 elafibranor. Most of 
them are of mild to moderate intensity. As previously, laboratory increases of serum 
creatinine or CPK should be monitored throughout clinical trials as this has been observed 
in Phase 2 II trials, and is a known PPARalpha agonist effect. Elevation of transaminases 
will be monitored as well as drug-induced liver injury. In the absence of human 
pregnancy data, double contraception should be maintained for women of childbearing 
potential participating in clinical trials with GFT505 elafibranor treatment, up to 1 month 
after end of study treatment. 
6.6.2 Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that 
support the therapeutic potential of elafibranor in metabolic diseases including 
NASH. Moreover, the Phase IIb trial demonstrated the efficacy of elafibranor at 
the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, 
resolution of histological NASH without worsening of fibrosis, in patients with 
active disease (NAS ≥4). While the trial was short and not designed for 
antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg daily, 
improved fibrosis indirectly through the resolution of NASH. Importantly, 
elafibranor 120 mg concomitantly improved the cardiometabolic risk profile of 
the patients by decreasing plasma triglycerides, total and LDL-cholesterol, 
increasing HDL-Cholesterol, and improving inflammation, insulin resistance, 
and glucose homeostasis. Together these results position elafibranor as a drug 
candidate to treat NASH with the objective to block fibrosis evolution and 


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ultimately avoid long term liver outcomes while reducing cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety 
concerns associated with elafibranor treatment, thus providing a favorable 
efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety 
Monitoring Board (DSMB) is established in order to review the safety of the 
treatment during the trial in an unblinded manner, to protect patient welfare 
and preserve study integrity. The safety assessments will be performed on a 
regular basis every 6 months after inclusion of the first patient. The DSMB 
consists of 4 experienced physicians (one endocrinologist, one cardiologist, one 
hepatologist, and one nephrologist) and one statistician, all independent of the 
participants in the study.  
In addition, throughout the study, patients will benefit from close safety 
monitoring including assessment of many safety parameters and follow-up of 
the disease progression mainly through noninvasive measures including 
fibroscan. 
10.1 CRF and 
source 
documents 
It is the Investigator’s obligation to ensure documentation of all relevant data in the 
patient’s medical file (medical history, concomitant diseases, patient identification 
number, date of informed consent, visit dates, administration of study medication, AEs 
[start and stop dates] and all concomitant medications [start and stop dates]). All data 
recorded in the eCRF will be documented by source data (e.g., but not limited to, 
doctors notes, X rays, hospital reports, or on any electronic device [ePRO]). 
If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any 
other kind of electronic devices) as part of regulated clinical trial activities, 
such systems must be compliant with all applicable laws and regulations 
governing use of electronic records and/or electronic signatures. Such systems 
may include, but are not limited to, electronic medical/health records, AE 
tracking/reporting, protocol-required assessments, and/or drug accountability 
records. 
 
 
Summary of minor changes to the protocol: 
The following minor changes were made to the protocol: 


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 
The version number and date were updated throughout the protocol 
 
Typographical and formatting errors were corrected throughout the protocol. 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
 
 


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Other secondary objectives 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Exploratory objectives 
 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 


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o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
 
Safety secondary objectives 
 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
 
NAS ≥4. 
 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine 
aminotransferase (ALT), obesity defined by a body mass index (BMI) 30, metabolic syndrome 
(NCEP ATP III definition), type 2 diabetes, or homeostasis model assessment of insulin resistance 
(HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
 
674 patients in placebo group 
 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
 
Screening Period: Week-12 to Week -1 prior to Randomization. 
 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 


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3. Body Mass Index ≤45 kg/m². 
4. Females participating in the study must either not be of childbearing potential (hysterectomy, 
bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation 
of menses for at least 12 months due to ovarian failure) or using efficient double contraception: 
hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device, or other 
mechanical contraception method + condom or diaphragm or spermicide for the full duration of the 
study and for 1 month after the end of treatment. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic 
acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in antidiabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e., implementation of a new antidiabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfamides, or insulin. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients. 
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol Consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 


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o 
positive hepatitis C Virus RNA) 
o 
suspicion of drug-induced liver disease 
o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
25. Positive anti-human immunodeficiency virus antibody. 
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. International normalized ratio >1.4. 
29. platelet count <100,000/mm3. 
30. Serum creatinine levels >135 µmol/L (>1.53 mg/dL) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 
repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 


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Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
 
liver transplantation 
 
MELD score ≥15 
 
HCC 
 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 


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Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
 
Regulatory/ethics committee submission: January 2016 
 
Initiation visits: February 2016 – March 2017 
 
Recruitment period: February 2016 – December 2017 
 
FPFV: February 2016 
 
Interim analysis : August – October 2018 
 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e. cardiovascular death, nonfatal myocardial, infarction, and stroke events as 
defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 








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8. 
Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, and IP compliance control. If any information during this phone contact 
requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up of patients having 
permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control).  
9. 
The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
10. ECG will be performed every 48 weeks starting at V9. 
11. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
12. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
13. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 






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= fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; 
NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing protein 3; PT  = 
prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = triglyceride; VLDL-C 
= very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period:  
 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test.  
 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 2 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 3 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 1.1 – SWEDEN: 29 JUNE 2016 .......................................................................................... 9 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 12 
TABLE OF CONTENTS ......................................................................................................................... 27 
TABLE OF TABLES .............................................................................................................................. 33 
TABLE OF FIGURES ............................................................................................................................ 34 
LIST OF ABBREVIATIONS .................................................................................................................... 35 
1. 
INTRODUCTION ................................................................................................................... 38 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 38 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 38 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 40 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 41 
1.4.1. 
Pharmacology ........................................................................................................... 41 
1.4.2. 
Safety pharmacology ................................................................................................. 42 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 42 
1.4.4. 
Toxicology ................................................................................................................ 43 
1.5. 
CLINICAL STUDIES ............................................................................................................... 44 
1.5.1. 
Phase I program ........................................................................................................ 44 
1.5.2. 
Phase II program ...................................................................................................... 45 
1.6. 
CONCLUSION ....................................................................................................................... 48 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 48 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 49 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 49 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 49 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 50 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 50 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 51 
2. 
TRIAL OBJECTIVES ............................................................................................................... 53 
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 53 
2.1.1. 
Surrogate endpoint -Interim analysis .......................................................................... 53 
2.1.2. 
Long-term endpoint ................................................................................................... 53 


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2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ............................................................... 53 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 54 
2.4. 
EXPLORATORY OBJECTIVES.................................................................................................. 54 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .......................................................................... 55 
2.6. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 55 
3. 
TRIAL DESIGN ..................................................................................................................... 57 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 57 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 57 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 58 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 58 
3.5. 
STUDY PERIODS .................................................................................................................. 58 
3.6. 
SCREENING PERIOD ............................................................................................................. 58 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .............. 58 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 60 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 60 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 60 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 61 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 61 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 62 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 62 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ................................................ 63 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 63 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 64 
3.11. OPTIONAL VISITS ................................................................................................................ 66 
3.11.1. 
Retesting screening visits ........................................................................................... 66 
3.11.2. 
Unscheduled visits ..................................................................................................... 66 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 66 
4. 
PATIENT SELECTION ............................................................................................................ 67 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 67 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 68 
5. 
TRIAL PROCEDURES ............................................................................................................. 71 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 71 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 71 
5.1.2. 
Dietary and fluid restrictions ....................................................................................... 71 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 72 
5.2.1. 
Handling of patient withdrawal ................................................................................... 72 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 72 
5.2.3. 
Patient discontinuation from the Study ........................................................................ 73 
5.2.4. 
Patients lost to follow-Up ........................................................................................... 74 


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5.2.5. 
Replacement ............................................................................................................. 74 
5.2.6. 
Premature discontinuation of the study ....................................................................... 74 
6. 
ASSESSMENTS ..................................................................................................................... 75 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 75 
6.1.1. 
Histological assessments ............................................................................................ 75 
6.1.2. 
Biological assessments ............................................................................................... 76 
6.1.3. 
Constitution of biobank .............................................................................................. 77 
6.1.4. 
Pharmacokinetics evaluation ...................................................................................... 77 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 78 
6.2.1. 
Physical examination.................................................................................................. 78 
6.2.2. 
Vital signs ................................................................................................................. 78 
6.2.3. 
Electrocardiogram...................................................................................................... 79 
6.2.4. 
FibroScan .................................................................................................................. 79 
6.2.5. 
Quality of life questionnaire ........................................................................................ 80 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 80 
6.3.1. 
Creatine phosphokinase ............................................................................................. 80 
6.3.2. 
Liver function monitoring ........................................................................................... 80 
6.3.3. 
Threshold for diagnostic of cirrhosis ............................................................................ 82 
6.4. 
SAFETY DATA REVIEW ......................................................................................................... 82 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 82 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 83 
6.6.1. 
Summary of safety data ............................................................................................. 83 
6.6.2. 
Benefit / risk assessment ........................................................................................... 85 
7. 
TREATMENTS ....................................................................................................................... 87 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 87 
7.2. 
PACKAGING AND LABELING .................................................................................................. 87 
7.2.1. 
Packaging ................................................................................................................. 87 
7.2.2. 
Labeling .................................................................................................................... 87 
7.2.3. 
Dosage and administration of Elafibranor and placebo ................................................. 88 
7.2.4. 
Prior and concomitant medications ............................................................................. 88 
7.3. 
STORAGE CONDITIONS ........................................................................................................ 88 
7.4. 
DISPENSING OF TREATMENT ................................................................................................ 88 
7.5. 
TREATMENT REPLACEMENT .................................................................................................. 89 
7.6. 
PROCEDURE FOR BLINDING ................................................................................................. 89 
7.7. 
PROCEDURE FOR UNBLINDING ............................................................................................. 89 
7.8. 
STUDY DRUG COMPLIANCE .................................................................................................. 90 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 90 
7.10. OTHER MEDICATION ............................................................................................................ 90 


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7.10.1. 
Handling of concomitant medication ........................................................................... 90 
7.10.2. 
Non-permitted medication .......................................................................................... 91 
7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) ............................................................................................................... 91 
7.10.4. 
Permitted medication ................................................................................................. 92 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 93 
8.1. 
DEFINITIONS ....................................................................................................................... 93 
8.1.1. 
Adverse event ........................................................................................................... 93 
8.1.2. 
Serious adverse events .............................................................................................. 94 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 95 
8.1.4. 
Adverse drug reaction ................................................................................................ 96 
8.1.5. 
Unexpected adverse event ......................................................................................... 96 
8.2. 
ASSESSMENTS ..................................................................................................................... 96 
8.2.1. 
Intensity assessment ................................................................................................. 96 
8.2.2. 
Relation to the study treatment .................................................................................. 97 
8.2.3. 
Action taken and outcome .......................................................................................... 97 
8.3. 
REPORTING ......................................................................................................................... 98 
8.3.1. 
Reporting an adverse event ....................................................................................... 98 
8.3.2. 
Reporting a serious adverse event .............................................................................. 98 
8.3.3. 
Follow-up ................................................................................................................ 100 
8.4. 
POST STUDY REPORTING REQUIREMENTS .......................................................................... 100 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS .............................................................................. 100 
8.6. 
SPECIAL SITUATION REPORTS ........................................................................................... 101 
8.6.1. 
Pregnancy ............................................................................................................... 101 
8.6.2. 
Medication error ...................................................................................................... 101 
8.6.3. 
Misuse .................................................................................................................... 101 
8.6.4. 
Overdose ................................................................................................................ 102 
8.6.5. 
Abuse ..................................................................................................................... 102 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ..................................................................... 103 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ............................................................... 103 
9.2. 
ENDPOINTS ....................................................................................................................... 103 
9.2.1. 
Surrogate endpoint - resolution of NASH ................................................................... 103 
9.2.2. 
Long-term endpoint – time to clinical event/death ..................................................... 103 
9.2.3. 
Key secondary endpoint ........................................................................................... 104 
9.2.4. 
Other secondary endpoints ...................................................................................... 104 
9.2.5. 
Exploratory endpoints .............................................................................................. 105 
9.3. 
ANALYSIS SETS .................................................................................................................. 105 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS.................................................................................... 106 


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9.4.1. 
Resolution of NASH.................................................................................................. 106 
9.4.2. 
Long-term endpoints ............................................................................................... 106 
9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................... 107 
9.5.1. 
Key secondary endpoint ........................................................................................... 107 
9.5.2. 
Other secondary endpoints ...................................................................................... 107 
9.5.3. 
Subgroup analyses .................................................................................................. 108 
9.5.4. 
Exploratory analyses ................................................................................................ 108 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 108 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 109 
9.7.1. 
Resolution of NASH.................................................................................................. 109 
9.7.2. 
Time to clinical event/death ..................................................................................... 109 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 110 
9.8.1. 
Interim analysis ....................................................................................................... 110 
9.9. 
BLINDED REASSESSMENT ................................................................................................... 111 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 112 
10.1. CRF AND SOURCE DOCUMENTS .......................................................................................... 112 
10.2. RETENTION OF RECORDS ................................................................................................... 113 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 114 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 114 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 115 
11.3. QUALITY ASSURANCE ......................................................................................................... 115 
12. 
ETHICS AND REGULATORY ................................................................................................. 116 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 116 
12.2. COMPETENT AUTHORITY ................................................................................................... 117 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 117 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 117 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 118 
13. 
FINANCING AND INSURANCE .............................................................................................. 119 
13.1. FINANCIAL ISSUES ............................................................................................................. 119 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 119 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 120 
14.1. STUDY REPORT .................................................................................................................. 120 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 120 
15. 
REFERENCES LIST .............................................................................................................. 122 
APPENDICES .................................................................................................................................... 125 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 126 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 135 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 136 


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APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 138 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 139 
 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 19 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 23 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 80 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 84 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
26 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
albumin–creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 


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HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNF 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 


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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)/ modulators with preferential activity on PPAR over 
PPAR (about fivefold more potent on human PPAR [hPPAR] than on hPPAR). The PPAR properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPAR 
response) and human hepatocytes (a mixed PPAR/ response). 
The PPAR receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPAR activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPAR compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPAR appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPAR agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPAR ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNF, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPAR knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNF, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPAR knockouts. 
Finally, in a short clinical trial, a pure PPAR agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing GT.16 


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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPAR 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPAR encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPAR and PPAR in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPAR-dependent and PPAR-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPAR reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPAR -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPAR 


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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPAR reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 


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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPAR-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPAR-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 


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1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor  has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV- Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 


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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 


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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 


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(-20% to -35%), reduction in low-density lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 


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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), Phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 


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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 


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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33  
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 


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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 


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 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
 
SAE, AE, physical examination, vital signs, medical history, ECG 
 
hematological parameters 
 
liver function parameters 
 
renal function parameters (including urinalysis) 


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 
cardiac function parameters 
 
metabolic parameters 
 
other biochemical safety markers. 
 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long-term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
 
Elafibranor 120 mg 
 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 


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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, and Figure 1. 
Schedule: 
 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
 
Signature of informed consent witnessed by the Investigator or designated person. 
 
Patient number allocation via IXRS. 
 
Check medical history/demographics. 
 
Check inclusion/exclusion criteria (described in Section 4). 
 
Physical examination (described in Section 6.2.1). 


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 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
 
Record vital signs (described in Section 6.2.2). 
 
Record height, weight, and waist circumference. 
 
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10 
and APPENDIX III: Permitted/Non-permitted medication) 
 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1. 
 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
 
Blood samples (described in Table 2). 
 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
 
Urinalysis dipstick. 
 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 31, 
and 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 2 digits corresponding to the site number (this number will be predefined), 
 Last 2 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
 
Check inclusion/exclusion criteria (detailed in Section 4). 
 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 


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 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference (V1, V3, V5, and V7, only). 
 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint  
described in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of 
the study following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 


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The following procedures will be performed at each visit from V8 to Vn: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
 
FibroScan (described in Section 6.2.4) 
 
Drug accountability 
 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety and IP compliance control. If any information during this phone contact requires a visit, 
the Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). IXRS 
registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 


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All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, and Figure 1. 
The following procedures will be performed at the EOT Visit: 
 
IXRS registration 
 
Physical examination (described in Section 6.2.1) 
 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
Quality of life assessment (described in Section 6.2.5) 
 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
 
Blood samples (described in Table 2) 
 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
 
Urinalysis and urinary dipstick (described in Table 2) 
 
Urinary pregnancy test (for WOCBP only) 
 
Record waist circumference 
 
12-lead ECG (described in Section 6.2.3) 
 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 


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including liver  and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
 
IXRS registration. 
 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
 
Reporting of any change in diet and life style factors 
 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 
 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 


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3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization. 
 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1). 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the Screening Period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral 
oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses 
for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal 
contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical 
contraception method + condom or diaphragm or spermicide for the full duration of the study and for 
1 month after the end of treatment. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 
treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or 
ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy.  
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions: 
 
No change in dose for patients treated by GLP-1 agonists 


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 
No qualitative change (i.e., implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfamides, or insulin. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients. 
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
 
Positive hepatitis B surface antigen (HBsAg) 
 
HCV RNA 
 
Suspicion of drug-induced liver disease 
 
Alcoholic liver disease 
 
Autoimmune hepatitis 


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 
Wilson’s disease hemochromatosis 
 
Primary biliary cirrhosis, primary sclerosing cholangitis 
 
Genetic hemochromatosis 
 
Known or suspected HCC 
 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g. 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
25. Positive anti-human immunodeficiency virus (HIV) antibody. 


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26. AST and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. INR >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, and 
Figure 1) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 


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 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 
The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 


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 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
 
Non-compliance with the study treatment 
 
Uncooperative patient 
 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 
At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 


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5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 


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6. 
ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
 
Needle core biopsy 
 
Biopsy obtained with a 16 or lower gage needle 
 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 


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The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
 
HIV ab I/II 
 
HBsAg 
 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
 
To discover or validate biomarkers in NASH and related diseases. 
 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 


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Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 


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6.2.2.1. 
Important points for clinical blood pressure measurement: 
 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT Visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 


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Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e., ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT Visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 
must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 


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For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
 
Increase in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 


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 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the 
Long-term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or ascites, 
then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will have to be 
adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e., cardiovascular death, nonfatal myocardial, infarction, and stroke 
events as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, 
consistent, and unbiased manner throughout the course of a study to determine whether the endpoints 
meet the protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 


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6.6. 
GUIDANCE FOR INVESTIGATORS 
6.6.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. 
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 


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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by Investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that Investigators review these lab results in 
the course of clinical trials. 


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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014). 
As such, all clinical trials with elafibranor including women of childbearing potential request a negative 
pregnancy test before Randomization, with effective contraceptive measures throughout the study. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between elafibranor and contraceptive steroids, the exclusive use of hormonal contraceptive methods 
during clinical trials should be avoided, and they should be accompanied by barrier methods. 
Conclusion on the safety data 
Based on the cumulative experience gathered to date, gastrointestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with elafibranor. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in Phase II trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
elafibranor treatment, up to 1 month after end of study treatment. 
6.6.2. 
Benefit / risk assessment 
Numerous Phase I and Phase IIa clinical studies have provided data that support the therapeutic potential 
of elafibranor in metabolic diseases including NASH. Moreover, the Phase IIb trial demonstrated the efficacy 
of elafibranor at the therapeutic dose of 120 mg on a clinically meaningful primary endpoint, resolution of 
histological NASH without worsening of fibrosis, in patients with active disease (NAS ≥4). While the trial 
was short and not designed for antifibrotic endpoints, it nonetheless showed that elafibranor, at 120 mg 
daily, improved fibrosis indirectly through the resolution of NASH. Importantly, elafibranor 120 mg 
concomitantly improved the cardiometabolic risk profile of the patients by decreasing plasma triglycerides, 
total and LDL-cholesterol, increasing HDL-Cholesterol, and improving inflammation, insulin resistance, and 
glucose homeostasis. Together these results position elafibranor as a drug candidate to treat NASH with the 


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objective to block fibrosis evolution and ultimately avoid long term liver outcomes while reducing 
cardiovascular risk.  
Moreover, clinical studies completed to date have not raised any major safety concerns associated with 
elafibranor treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
Despite this favorable benefit-risk profile, an independent Data Safety Monitoring Board (DSMB) is 
established in order to review the safety of the treatment during the trial in an unblinded manner, to 
protect patient welfare and preserve study integrity. The safety assessments will be performed on a regular 
basis every 6 months after inclusion of the first patient. The DSMB consists of 4 experienced physicians 
(one endocrinologist, one cardiologist, one hepatologist, and one nephrologist) and one statistician, all 
independent of the participants in the study.  
In addition, throughout the study, patients will benefit from close safety monitoring including assessment of 
many safety parameters and follow-up of the disease progression mainly through noninvasive measures 
including fibroscan. 
 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 


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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 


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value defined in the supply strategy. Following Randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 


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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
 
Blister identification 
 
Quantity destroyed 
 
Method of destruction 
 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 


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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
 
Glitazones (pioglitazone & rosiglitazone) 
 
Fibrates 
 
Corticosteroids (parenteral & oral chronic administration only) 
 
Amiodarone 
 
Tamoxifen 
 
Methotrexate 
 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 


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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfamides 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfamides and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
 
Test result is associated with accompanying symptoms 
 
Test result requires additional diagnostic testing or medical/surgical intervention 
 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
 
Overdose without clinical sequelae 


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 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
 
Uncomplicated pregnancy 
 
An induced elective abortion to terminate a pregnancy without medical reason 
 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (see Section 8.1.2.1) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 


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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
 
Hospitalization for survey visits or annual physicals fall in the same category. 
 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias or convulsions that do not result in hospitalization 
 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
 
As an outcome event, progression to cirrhosis should not be included as AE. 
 
Death is an outcome of an AE, not an AE in itself. 


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 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 


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 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
 
Dose not changed – in case no action is taken regarding the study drug 


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 
Unknown 
 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
 
Recovered/resolved 
 
Recovering/resolving 
 
Not recovered/not resolved 
 
Recovered/resolved with sequelae 
 
Fatal 
 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
the last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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 
SAEs (including events related to study procedures) 
 
SADRs 
 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
 
Type 2 diabetes (yes, no) 
 
Gender (male, female) (with a capping of women to 40%) 
 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 


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 
Liver transplantation 
 
MELD score ≥15 
 
HCC 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key secondary endpoint 
The key secondary endpoint is: 
 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other secondary endpoints 
The other secondary endpoints are: 
 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 


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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 


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 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS. 
 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
 
Full Intent-To-Treat Set (FITT): all randomized patients. 
 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS,and exploratory F1 cohorts (study population and efficacy data) will analyzed 
based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts (safety 
data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 


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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 


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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
 
Presence of type 2 diabetes (yes, no) 
 
Gender (male, female) 
 
Fibrosis (F2, F3) 
 
Geographic region (North America, Europe, South America, Rest of World) 
 
Race (Caucasian, Hispanic, Other) 
 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided =0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided =0.01 for resolution of NASH and two-sided =0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided =0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided =0.01 for resolution of NASH and 
two-sided =0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided =0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
 
=0.01 two-sided 
 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
 
Pooled variance 
 
Randomization ratio of 2:1 (elafibranor: placebo) 
 
8% response in the control group 
 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
 
72 month maximum follow-up 
 
=0.04 two-sided 
 
Annual event rate of 7% for the placebo group 
 
Hazard ratio of 0.75 in favor of the elafibranor group 
 
4% annual drop-out rate over 72 months 
 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 


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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e., 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 


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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11.  
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate, and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data (e.g., but not limited to, 
doctors notes, X rays, hospital reports, or on any electronic device [ePRO]). 
If source data are created (first entered), modified, maintained, archived, retrieved, or transmitted 
electronically via computerized systems (and/or any other kind of electronic devices) as part of regulated 
clinical trial activities, such systems must be compliant with all applicable laws and regulations governing 
use of electronic records and/or electronic signatures. Such systems may include, but are not limited to, 
electronic medical/health records, AE tracking/reporting, protocol-required assessments, and/or drug 
accountability records. 


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10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 
The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical Investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
pregnancy 
testing 
in 
clinical 
trials. 
Available 
at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 


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Appendices 


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APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X 
 












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CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to 
Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic 
Steatohepatitis (NASH) and fibrosis. 
PROTOCOL NUMBER: GFT505-315-1 
EudraCT Number:  
2015-005385-38 
IND Number:  
115028 
CLINICAL PHASE: 
3 
VERSION: 
1. 1 United Kingdom 
DATE: 
May 17, 2016 
SPONSOR: 
GENFIT, 
 
Parc Eurasanté, 
 
885 Avenue Eugène Avinée, 
 
59120 LOOS - France 
 
In signing below, I confirm having read the protocol, and give agreement to the protocol. 
INVESTIGATOR NAME: 
_______________________________________ 
 
INSTITUTION NAME: 
_______________________________________ 
 
INSTITUTION ADDRESS: 
_______________________________________ 
 
 
  
_______________________________________ 
 
 
SIGNATURE: 
  
_______________________________________ 
DATE: 
  
_____ /_______ /________ 
 
  
Day  
 Month 
 Year 
 


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STUDY CONTACTS 
Protocol N°:  
GFT505-315-1/ EudraCT N° 2015-005385-38/ IND n° 115028 
International 
Coordinating 
Investigator 
Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IXRS  
 
 
 
 
  
 
 
 
 
 
 
 
Study drug 
supplier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central pathology 
laboratory 
 
 
 
 
 
 
 
ePRO 
 
 
 
 
 
 
 
 
 
 
 


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AMENDMENT 1 – UNITED KINGDOM: 17 MAY 2016 
Amendment 1 – United Kingdom addresses the grounds for non-acceptance from the Medicines and 
Healthcare Products Regulatory Agency (MHRA) dated 06 May 2016. 
Revisions were made to protocol sections noted below as well as to the study synopsis, the study schedule 
of assessments (Table 1), study biological assessment schedule (Table 2), and study duration and visit 
schedule (Figure 1). Added text is bolded; deleted text is struck through. 
Summary of major changes to the protocol: 
Section 
New Text 
Figure 1 
Removal of ECG during V8 for consistency with Table 1 and text and addition of home 
pregnancy test results to PV. 
 


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Figure 2 
New figure included for pregnancy testing schedule for women of childbearing potential. 
 
Section 3.7.2 
First 
Treatment 
Period visits 
V1 to V7 
(Week 0 to 
Week 72) 
 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 
and APPENDIX II: Adequate diet and lifestyle recommendations), alcohol 
restrictions (described in Section 5.1.2), and tobacco habits 
• 
Check concomitant/prior medication (described in Section 7.10 and APPENDIX 
III: Permitted/Non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) 
(described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed ever 4 week 
[see Figure 2]) since previous visit (for WOCBP only, every visit from 
V2) 


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• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
• 
Drug accountability (every visit from V2). 
Section 3.8.1 
Long-term 
Treatment 
Period 
visits 
(V8 to Vn) 
 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. 
The patient will be contacted at least 1 week before each visit to be reminded of 
procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 
and APPENDIX II: Adequate diet and lifestyle recommendations), alcohol 
restrictions (described in Section 5.1.2), and tobacco habits 
• 
Check concomitant/prior medication (described in Section 7.10 and APPENDIX 
III: Permitted/Non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and 
Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4, with the exception 
of the final Vn visit) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF 
informed consent signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record results of home pregnancy tests (to be performed every 
4 weeks [see Figure 2]) since previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
• 
FibroScan (described in Section 6.2.4) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver 
cirrhosis, described in Section 6.1.1). Liver biopsy samples will be sent for central 
histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in 


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Table 2) and tested at a local laboratory prior to the liver biopsy. 
Section 3.8.2 
Long-term 
Treatment 
Period phone 
visits (PV1 to 
PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data 
collection on clinical outcomes, safety, home pregnancy test results, and IP 
compliance control. If any information during this phone contact requires a visit, the 
Investigator may decide to perform an unscheduled visit (described in Section 3.11.2). 
IXRS registration will be performed for each phone visit. 
Section 3.9 
End of Study 
Treatment 
Visit 
 
The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Check concomitant/prior medication (described in Section 7.10 and APPENDIX 
III: Permitted/Non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.5) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and 
Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF 
informed consent signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record results of home pregnancy tests (to be performed every 
4 weeks [see Figure 2]) since previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.3) 
• 
Drug accountability. 
Section 4.1 
Inclusion 
criteria 
• 
no qualitative change (i.e., implementation of a new antidiabetic therapy) for 
patients treated by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose 
cotransporter 2 (SGLT2) inhibitors, sulfonylurea medications sulfamides, or insulin. 
Section 
5.1.3 Ultra-
violet light 
exposure 
As a conservative approach patients will be advised to avoid extended ultra-
violet light exposure without protection from SV1 through to the end of the 
study (Section 1.4.4.4). 
Section 
5.1.4 Home 
pregnancy 
Women of childbearing potential are required to perform a pregnancy test 
every 4 weeks. Home pregnancy test kits will be supplied at each visit to 
WOCBP and these are to be performed as per the kit instructions every 




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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT 
 
Study Drug: 
Elafibranor (GFT505): Propanoic acid, 2-
[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-
3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid 
Protocol Number: 
GFT505-315-1 
Title of the study: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and 
Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis 
Phase: 
Phase III 
Indication: 
NASH 
Study design and dose levels: 
Randomized, double-blind, parallel groups (placebo or elafibranor [GFT505]) placebo-controlled study, 
evaluating the efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population 
with fibrosis. The first double-blind 72-week treatment period will assess the efficacy and safety of 
elafibranor on the resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, 
followed by a Long-term Treatment Period to assess efficacy on all-cause mortality and liver-related clinical 
outcomes as measured by the time to first occurrence of any of the listed adjudicated events (all-cause 
mortality, progression to histological cirrhosis, and the full list of portal hypertension/cirrhosis related 
events). 
Dose level 
120 mg 
Route of administration: 
Oral (1 tablet once daily [QD])  
Primary objectives – surrogate endpoint (at interim analysis) 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence 
of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for 
steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
 
Primary objectives – long-term endpoints 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 
death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed, 
o 
hepatic encephalopathy, 
o 
spontaneous bacterial peritonitis, 
o 
uncontrolled ascites, 
o 
hepatorenal syndrome, 
o 
hepatopulmonary syndrome, 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
 
Key secondary objective (at interim analysis) 
To assess histological changes after 72 weeks of treatment on the following endpoint parameter: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 
 
Other secondary objectives 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 


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parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total nonalcoholic fatty liver disease (NAFLD) activity score (NAS), steatosis, 
hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal 
inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire) 
• 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
Exploratory objectives 
• 
To determine pharmacokinetic (PK) parameters of elafibranor (GFT505) and GFT1007 after 
72 weeks of treatment for PK population analyses. 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
 
Exploratory objectives for F1 group 
• 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite long-term endpoints 
o 
cardiovascular events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 


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o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
• 
To assess the tolerability and safety. 
 
Safety secondary objectives 
• 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 
120 mg description of: 
o 
serious adverse events, adverse events, physical examination, vital signs, medical history, 
electrocardiogram 
o 
hematological parameters 
o 
liver function parameters 
o 
renal function parameters (including urinalysis) 
o 
cardiac function parameters 
o 
metabolic parameters 
o 
other biochemical safety markers. 
Patient population: 
NASH diagnosed as: 
Steatohepatitis evaluated by a centrally-read liver biopsy taken within 6 months prior to Randomization (if 
no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed during the Screening 
Period) with: 
• 
At least a score of 1 in each component of the NAS score (steatosis scored 0-3, ballooning 
degeneration scored 0-2, and lobular inflammation scored 0-3). 
• 
NAS ≥4. 
• 
fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included, meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated alanine aminotransferase 
(ALT), obesity defined by a body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III 
definition), type 2 diabetes, or homeostasis model assessment of insulin resistance (HOMA-IR) >6. 
At the end of the 72-week treatment period, patients will continue in the double-blind Long-term Treatment 
Period. Patients will be monitored by notably measuring the potential appearance of cirrhosis (based on 
FibroScan measurement for presence of cirrhosis associated with biological and clinical assessments and 
confirmed by biopsy). If histological cirrhosis is confirmed as well as any other event listed in the long-term 
composite endpoint, patients will be discontinued from study. 
Number of estimated randomized F2-F3 Patients: total 2022 patients (ratio 2:1) 
• 
674 patients in placebo group 
• 
1348 patients in elafibranor (GFT505) group 
 
An additional 202 (10% of the F2-F3 patients) F1 patients at high risk of progression will be included as an 
exploratory arm. 
Number of participating centers (planned): ~200 centers 
Number of participating countries: ~20 (Belgium, France, Germany, Italy, the Netherlands, Romania, Spain, 
UK, Switzerland, Portugal, Denmark, Finland, Sweden, Czech republic, Russia, Turkey, USA, Canada, 
Colombia, Brazil, Argentina, Chile, Australia, South Africa) 
Study duration per patient: 
Estimated duration approximately 72 months, based on 456 patients experiencing a long-term composite 
endpoint event. 
Schedule: 
• 
Screening Period: Week-12 to Week -1 prior to Randomization. 
• 
First Treatment Period: Week 0 to Week 72: period of treatment with elafibranor (GFT505) or 
placebo for 72 weeks. 
• 
Long-term Treatment Period: Week 72 to end of study: extension of treatment with elafibranor 
(GFT505) or placebo (until occurrence of prespecified number of events). 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. Must provide signed written informed consent and agree to comply with the study protocol. 
3. Body Mass Index ≤45 kg/m². 
4. Females participating in the study must either not be of childbearing potential (hysterectomy, 


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bilateral oophorectomy, medically documented ovarian failure, or >50 years of age with cessation 
of menses for at least 12 months due to ovarian failure) or using efficient double contraception: 
hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device, or other 
mechanical contraception method + condom or diaphragm or spermicide for the full duration of the 
study and for 1 month after the end of treatment. 
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the 
slides (biopsy obtained within 6 months prior to Randomization or during the Screening Period) with 
at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration 
scored 0-2, and lobular inflammation scored 0-3). 
6. NAS score ≥4. 
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score ≥5 and 2 of the following conditions: persistent elevated ALT, obesity defined by 
a BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks 
of treatment for assessment of the treatment effects on NASH, as well as another in case of 
suspicion of cirrhosis (to have a histological confirmation), and a final liver biopsy after 
approximately 4 years of treatment (visit V13), unless a biopsy has already been performed within 
the year. 
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic 
acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
antidiabetic drugs, no change in antidiabetic therapy is allowed within 6 months prior to diagnostic 
liver biopsy, under the following conditions: 
o 
no change in dose for patients treated by glucagon-like peptide 1 agonist 
o 
no qualitative change (i.e., implementation of a new antidiabetic drug) for patients treated 
by metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 inhibitors, 
sulfonylurea medications, or insulin. 
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. Known heart failure (Grade I to IV of New York Heart Association classification). 
2. History of efficient bariatric surgery within 5 years prior to Screening. 
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. Type 1 diabetes patients. 
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first 
Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to 
Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued 
at least 6 months before the diagnostic liver biopsy. 
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. Weight loss of more than 5% within 6 months prior to Randomization. 
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). 
Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system 
are excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan 
to donate blood or blood products at any time during the trial and in the 2 months following the 
end of the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
o 
positive hepatitis B surface antigen 
o 
positive hepatitis C Virus RNA) 
o 
suspicion of drug-induced liver disease 


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o 
alcoholic liver disease 
o 
autoimmune hepatitis 
o 
Wilson’s disease hemochromatosis 
o 
primary biliary cirrhosis, primary sclerosing cholangitis 
o 
genetic hemochromatosis 
o 
known or suspected HCC 
o 
history or planned liver transplant, or current MELD score >12 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with 
the recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, 
prior to Screening. 
 
Concomitant medications: 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 
months prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization. 
 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be 
compliant with the study is uncertain. 
 
In addition to the above criteria, patient should not present any of the following biological exclusion criteria: 
25. Positive anti-human immunodeficiency virus antibody. 
26. Aspartate aminotransferase (AST) and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. International normalized ratio >1.4. 
29. platelet count <100,000/mm3. 
30. Serum creatinine levels >135 µmol/L (>1.53 mg/dL) in males and >110 µmol/L (>1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 
60 ml/min/1.73 m2). If abnormal at the first Screening Visit, the eGFR measurement can be 
repeated prior to the Randomization within the following timeframe: minimum 4 weeks after initial 
test and maximum 2 weeks prior to planned Randomization. A repeated abnormal eGFR (less than 
60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum creatine phosphokinase (CPK) >3 x the ULN. In case of explained elevated CPK 
>3 x the ULN, the measurement can be repeated prior to Randomization. In this case, retest should 
be performed within 1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
Criteria for Evaluation: 
Primary endpoint 
Surrogate endpoint - resolution of NASH (at interim analysis) 
The resolution of NASH without worsening of fibrosis after 72 weeks of treatment with elafibranor. 
 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed of 


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death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 
• 
liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites, hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected to 
occur approximately 72 months after the first patient is randomized. 
 
Key secondary endpoint (at interim analysis) 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 
72 weeks. 
 
Other secondary endpoints 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF score, and activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NAFLD CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72, 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
Study Duration (planned): estimated 72 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: January 2016 
• 
Initiation visits: February 2016 – March 2017 
• 
Recruitment period: February 2016 – December 2017 
• 
FPFV: February 2016 
• 
Interim analysis : August – October 2018 
• 
LPLV (Long-term treatment period): December 2021 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will be established in order to review the progress of the study and to perform a 


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safety data review on a regular basis during the trial to protect patient welfare and preserve study integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
Clinical events committee (CEC) 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy endpoint (except for histological cirrhosis), all drug-induced liver injury events, and all 
major cardiovascular events: i.e., cardiovascular death, nonfatal myocardial, infarction, and stroke events 
as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, consistent, and 
unbiased manner throughout the course of a study to determine whether the endpoints meet the 
protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 
 








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4. 
Women of child bearing potential are required to perform a pregnancy test every 4 weeks from the start of treatment until the EOT Visit. This test will be performed at home using a 
kit supplied by the site for the weeks when there are no scheduled visits (Weeks 4, 8, 16, 20, 28, 32, 40, 44, 52, 56, 64, and 68 in the First Treatment Period and Weeks 76, 80, 84, 
88, 92, 100, 104, 108, 112, 116 etc. in the Long-term Treatment Period). 
5. 
Negative results of home pregnancy tests performed by WOCBA are confirmed and recorded during scheduled visits or telephone visits. In the case of a positive result, the patient 
must discontinue study drug immediately and inform the Investigator as soon as possible. 
6. 
This visit only occurs if no historical biopsy within 6 months before the Randomization Visit is available. A screening liver biopsy and slides shipment to the central 
anatomopathologist must be performed at least 4 weeks before Randomization (in order to obtain the results in time). Coagulation (platelet count and PT [INR]) should be checked 
locally prior to this liver biopsy (according to local medical standards in each hospital). 
7. 
Screening Phone Visit. Telephone contact for all patients at least 1 week before V1. Patients should be contacted regarding eligibility confirmation within 1 week prior to 
Randomization Visit V1. In case of ineligibility, the patient should be contacted as soon as possible. 
8. 
The maximum time period between visits in the First Treatment Period is to be 96 days due to the study drug supply provided to the patient. 
9. 
Check of all inclusion/exclusion criteria, including biological and histological criteria assessed at SV1 and SV2. 
10. Phone visits every 24 weeks starting 12 weeks after V7 for safety, data collection on clinical outcomes, home pregnancy test results, and IP compliance control. If any information 
during this phone contact requires a visit, the Investigator may decide to perform an unscheduled visit. Phone visits may also be performed at the same frequency for the follow-up 
of patients having permanently discontinued study drug but remaining in the study (Same information collected except IP compliance control). 
11. The maximum time period between visits in the Long-term Treatment Period is to be 192 days due to the study drug supply provided to the patient. 
12. ECG will be performed every 48 weeks starting at V9. 
13. Liver biopsy will be performed after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or biological assessment). 
In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after approximately 4 years of 
treatment (V13, unless a biopsy has already been performed within the year). Blood sampling (coagulation tests; see Table 2) are to be performed locally before the biopsy. 
14. QOL assessment questionnaire to be completed at 24 (V8), 48 (V9), and 96 (V11) weeks in the Long-term Treatment Period (following approximately 96, 120, and 168 weeks of 
treatment, respectively), and 48 weekly thereafter. 
15. EOT Visit to be performed 30 days after final study drug administration at the end of study or for any premature discontinuation (permanent study drug discontinuation or trial 
discontinuation). 






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= fatty liver index; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL-C = high-density lipoprotein-C; HIV = 
human immunodeficiency virus; HOMA-IR = homeostasis model assessment of insulin resistance; hsCRP = high-sensitivity C-reactive protein; IL-18 = interleukin 18; INR = international 
normalized ratio; KIM-1 = kidney injury molecule-1; LDL-c = low density lipoprotein-C; NAFLD = nonalcoholic fatty liver disease; N-Gal = neutrophil gelatinase-associated lipocalin; 
NT-ProBNP = N-terminal of the prohormone brain natriuretic peptide; PIIINP = type III procollagen peptide; PNPLA3 = patatin-like phospholipase domain-containing protein 3; PT = 
prothrombin time; TIMP-1 = tissue inhibitors of metalloproteinases 1; RBC = red blood cell; SBx = Screening biological assessment Visit x; SVx = Screening Visit x; TG = triglyceride; VLDL-C 
= very low density lipoprotein-C; Vx = Visit; WBC = white blood cell. 
1. 
Coagulation (platelet count and PT [INR]) should be checked prior to any liver biopsy (according to local medical standards in each hospital). To be done through a local laboratory. 
Liver biopsy will be performed after 72 weeks (V7) and after approximately 4 years of treatment (V13) and in the case of suspicion of cirrhosis (based on FibroScan and/or clinical or 
biological assessment). In the case that the suspicion of cirrhosis is not confirmed by liver biopsy the patient shall remain on the study and a liver biopsy will be performed after 
approximately 4 years of treatment ([V13] unless a biopsy has already been performed within the year). 
2. 
Upon receipt of the results of the biological assessment performed at SV1, retesting or additional testing may be needed during the Screening Period: 
• 
CPK can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
• 
The eGFR measurement can be repeated prior to Randomization (V1) within the following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to 
planned Randomization. 
• 
HbA1c can be repeated prior to Randomization (V1), at the latest 2 weeks prior to planned Randomization. 
• 
HCV RNA, in case of positive HCV Ab, at the latest 2 weeks prior to the planned Randomization (V1). 
3. 
Dipstick at site for WOCBP only. In addition, home pregnancy tests are to be performed by WOCBP every 4 weeks (see Table 1 and Figure 2). 
4. 
CHI3L1 to be tested only at V1, V7, and at the time of 4 years biopsy (V13). 
5. 
Whole blood sample will be only taken at SV1 for the analysis of PNPLA3 following DNA extraction. Plasma and serum samples should be retrieved at every visit ONLY for patients 
who have signed the genetic and biomarker ICF. 
6. 
For DILI adjudication, to ensure adequate baseline value of the liver parameters (AST, ALT, total bilirubin, INR), at least 2 consecutive assessments at least 8 weeks apart between 
Visit SV1 and Visit V1 should be performed. SV1 and Visit V1 should be scheduled according to this requirement. 
7. 
SB2, additional visit in the Screening Period if required for coagulation prior to liver biopsy. 
 
 


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Figure 1: 
STUDY DURATION AND VISIT SCHEDULE 
 


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Figure 2: 
PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
 CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 2 
 CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 3 
 CLINICAL STUDY PROTOCOL SIGNATURE PAGE .................................................................................... 4 
CLINICAL STUDY PROTOCOL SIGNATURE PAGE ..................................................................................... 5 
CLINICAL STUDY PROTOCOL INVESTIGATOR SIGNATURE PAGE ............................................................. 6 
STUDY CONTACTS ................................................................................................................................ 7 
AMENDMENT 1 – UNITED KINGDOM: 17 MAY 2016 ................................................................................ 9 
CLINICAL TRIAL SYNOPSIS ................................................................................................................. 14 
TABLE OF CONTENTS ......................................................................................................................... 30 
TABLE OF TABLES .............................................................................................................................. 36 
TABLE OF FIGURES ............................................................................................................................ 37 
LIST OF ABBREVIATIONS .................................................................................................................... 38 
1. 
INTRODUCTION ................................................................................................................... 41 
1.1. 
NONALCOHOLIC STEATOHEPATITIS ..................................................................................... 41 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS ............................. 41 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH .................. 43 
1.4. 
SUMMARY OF NONCLINICAL STUDIES ................................................................................... 44 
1.4.1. 
Pharmacology ........................................................................................................... 44 
1.4.2. 
Safety pharmacology ................................................................................................. 45 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) ...................................... 45 
1.4.4. 
Toxicology ................................................................................................................ 46 
1.5. 
CLINICAL STUDIES ............................................................................................................... 47 
1.5.1. 
Phase I program ........................................................................................................ 47 
1.5.2. 
Phase II program ...................................................................................................... 48 
1.6. 
CONCLUSION ....................................................................................................................... 51 
1.7. 
RATIONALE FOR STUDY POPULATION ................................................................................... 51 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE .............................................................................. 52 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT .................................................................................. 52 
1.9.1. 
Primary endpoint for application under conditional approval ......................................... 52 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation)................................ 53 
1.10. RATIONALE FOR STUDY DURATION ...................................................................................... 53 
1.11. RATIONALE FOR SAFETY MONITORING ................................................................................. 54 
2. 
TRIAL OBJECTIVES ............................................................................................................... 56 
2.1. 
PRIMARY OBJECTIVES .......................................................................................................... 56 
2.1.1. 
Surrogate endpoint -Interim analysis .......................................................................... 56 
2.1.2. 
Long-term endpoint ................................................................................................... 56 


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2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS ............................................................... 56 
2.3. 
OTHER SECONDARY OBJECTIVES ......................................................................................... 57 
2.4. 
EXPLORATORY OBJECTIVES.................................................................................................. 57 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP .......................................................................... 58 
2.6. 
SAFETY SECONDARY OBJECTIVES ......................................................................................... 58 
3. 
TRIAL DESIGN ..................................................................................................................... 60 
3.1. 
NUMBER OF PATIENTS ......................................................................................................... 60 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .................................................... 60 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................. 61 
3.4. 
DURATION OF STUDY PARTICIPATION ................................................................................. 61 
3.5. 
STUDY PERIODS .................................................................................................................. 61 
3.6. 
SCREENING PERIOD ............................................................................................................. 61 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to Week -4): .............. 61 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): ............................. 63 
3.6.3. 
Screening Phone Visit SPV (Week -1): ......................................................................... 63 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) ............................................................... 63 
3.7.1. 
Randomization Visit V1 (Week 0): ............................................................................... 64 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72):........................................ 64 
3.8. 
LONG-TERM TREATMENT PERIOD ......................................................................................... 65 
3.8.1. 
Long-term Treatment Period visits (V8 to Vn) .............................................................. 66 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) ................................................ 66 
3.9. 
END OF STUDY TREATMENT VISIT........................................................................................ 67 
3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG ........... 68 
3.11. OPTIONAL VISITS ................................................................................................................ 69 
3.11.1. 
Retesting screening visits ........................................................................................... 69 
3.11.2. 
Unscheduled visits ..................................................................................................... 69 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY .................................................................................. 69 
4. 
PATIENT SELECTION ............................................................................................................ 70 
4.1. 
INCLUSION CRITERIA ........................................................................................................... 70 
4.2. 
EXCLUSION CRITERIA .......................................................................................................... 71 
5. 
TRIAL PROCEDURES ............................................................................................................. 74 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS ........................................ 74 
5.1.1. 
Standard diet and exercise recommendations .............................................................. 74 
5.1.2. 
Dietary and fluid restrictions ....................................................................................... 74 
5.1.3. 
Ultra-violet light exposure .......................................................................................... 75 
5.1.4. 
Home pregnancy test for women of childbearing potential ........................................... 75 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ..................... 75 
5.2.1. 
Handling of patient withdrawal ................................................................................... 75 
5.2.2. 
Permanent discontinuations of study drug ................................................................... 75 


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5.2.3. 
Patient discontinuation from the Study ........................................................................ 76 
5.2.4. 
Patients lost to follow-Up ........................................................................................... 77 
5.2.5. 
Replacement ............................................................................................................. 77 
5.2.6. 
Premature discontinuation of the study ....................................................................... 77 
6. 
ASSESSMENTS ..................................................................................................................... 79 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS .................................................................................. 79 
6.1.1. 
Histological assessments ............................................................................................ 79 
6.1.2. 
Biological assessments ............................................................................................... 80 
6.1.3. 
Constitution of biobank .............................................................................................. 81 
6.1.4. 
Pharmacokinetics evaluation ...................................................................................... 81 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .................................... 82 
6.2.1. 
Physical examination.................................................................................................. 82 
6.2.2. 
Vital signs ................................................................................................................. 82 
6.2.3. 
Electrocardiogram...................................................................................................... 83 
6.2.4. 
FibroScan .................................................................................................................. 83 
6.2.5. 
Quality of life questionnaire ........................................................................................ 84 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES
 ........................................................................................................................................... 84 
6.3.1. 
Creatine phosphokinase ............................................................................................. 84 
6.3.2. 
Liver function monitoring ........................................................................................... 84 
6.3.3. 
Threshold for diagnostic of cirrhosis ............................................................................ 86 
6.4. 
SAFETY DATA REVIEW ......................................................................................................... 86 
6.5. 
CLINICAL EVENT COMMITTEE ............................................................................................... 86 
6.6. 
GUIDANCE FOR INVESTIGATORS .......................................................................................... 87 
7. 
TREATMENTS ....................................................................................................................... 90 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................... 90 
7.2. 
PACKAGING AND LABELING .................................................................................................. 90 
7.2.1. 
Packaging ................................................................................................................. 90 
7.2.2. 
Labeling .................................................................................................................... 90 
7.2.3. 
Dosage and administration of Elafibranor and placebo ................................................. 91 
7.2.4. 
Prior and concomitant medications ............................................................................. 91 
7.3. 
STORAGE CONDITIONS ........................................................................................................ 91 
7.4. 
DISPENSING OF TREATMENT ................................................................................................ 91 
7.5. 
TREATMENT REPLACEMENT .................................................................................................. 92 
7.6. 
PROCEDURE FOR BLINDING ................................................................................................. 92 
7.7. 
PROCEDURE FOR UNBLINDING ............................................................................................. 92 
7.8. 
STUDY DRUG COMPLIANCE .................................................................................................. 93 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 93 
7.10. OTHER MEDICATION ............................................................................................................ 93 


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7.10.1. 
Handling of concomitant medication ........................................................................... 93 
7.10.2. 
Non-permitted medication .......................................................................................... 94 
7.10.3. 
Permitted medication under condition (see APPENDIX III: Permitted/Non-permitted 
medication) ............................................................................................................... 94 
7.10.4. 
Permitted medication ................................................................................................. 95 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT .................................................................... 96 
8.1. 
DEFINITIONS ....................................................................................................................... 96 
8.1.1. 
Adverse event ........................................................................................................... 96 
8.1.2. 
Serious adverse events .............................................................................................. 97 
8.1.3. 
Clarification on serious adverse events: ...................................................................... 98 
8.1.4. 
Adverse drug reaction ................................................................................................ 99 
8.1.5. 
Unexpected adverse event ......................................................................................... 99 
8.2. 
ASSESSMENTS ..................................................................................................................... 99 
8.2.1. 
Intensity assessment ................................................................................................. 99 
8.2.2. 
Relation to the study treatment ................................................................................ 100 
8.2.3. 
Action taken and outcome ........................................................................................ 100 
8.3. 
REPORTING ....................................................................................................................... 101 
8.3.1. 
Reporting an adverse event ..................................................................................... 101 
8.3.2. 
Reporting a serious adverse event ............................................................................ 101 
8.3.3. 
Follow-up ................................................................................................................ 103 
8.4. 
POST STUDY REPORTING REQUIREMENTS .......................................................................... 103 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS ADVERSE 
EVENTS OR SERIOUS ADVERSE EVENTS .............................................................................. 103 
8.6. 
SPECIAL SITUATION REPORTS ........................................................................................... 104 
8.6.1. 
Pregnancy ............................................................................................................... 104 
8.6.2. 
Medication error ...................................................................................................... 104 
8.6.3. 
Misuse .................................................................................................................... 104 
8.6.4. 
Overdose ................................................................................................................ 105 
8.6.5. 
Abuse ..................................................................................................................... 105 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ..................................................................... 106 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ............................................................... 106 
9.2. 
ENDPOINTS ....................................................................................................................... 106 
9.2.1. 
Surrogate endpoint - resolution of NASH ................................................................... 106 
9.2.2. 
Long-term endpoint – time to clinical event/death ..................................................... 106 
9.2.3. 
Key secondary endpoint ........................................................................................... 107 
9.2.4. 
Other secondary endpoints ...................................................................................... 107 
9.2.5. 
Exploratory endpoints .............................................................................................. 108 
9.3. 
ANALYSIS SETS .................................................................................................................. 108 
9.4. 
ANALYSIS OF PRIMARY ENDPOINTS.................................................................................... 109 


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9.4.1. 
Resolution of NASH.................................................................................................. 109 
9.4.2. 
Long-term endpoints ............................................................................................... 109 
9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................... 110 
9.5.1. 
Key secondary endpoint ........................................................................................... 110 
9.5.2. 
Other secondary endpoints ...................................................................................... 110 
9.5.3. 
Subgroup analyses .................................................................................................. 111 
9.5.4. 
Exploratory analyses ................................................................................................ 111 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ........................................................................... 111 
9.7. 
SAMPLE SIZE CALCULATION ............................................................................................... 112 
9.7.1. 
Resolution of NASH.................................................................................................. 112 
9.7.2. 
Time to clinical event/death ..................................................................................... 112 
9.8. 
SAFETY ANALYSIS .............................................................................................................. 113 
9.8.1. 
Interim analysis ....................................................................................................... 113 
9.9. 
BLINDED REASSESSMENT ................................................................................................... 114 
10. 
DATA HANDLING AND RECORD KEEPING ............................................................................ 115 
10.1. CRF AND SOURCE DOCUMENTS .......................................................................................... 115 
10.2. RETENTION OF RECORDS ................................................................................................... 115 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 117 
11.1. QUALITY CONTROL & MONITORING PROCEDURES .............................................................. 117 
11.2. ETHICAL PRINCIPLES ......................................................................................................... 118 
11.3. QUALITY ASSURANCE ......................................................................................................... 118 
12. 
ETHICS AND REGULATORY ................................................................................................. 119 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................................. 119 
12.2. COMPETENT AUTHORITY ................................................................................................... 120 
12.3. PATIENT INFORMATION AND CONSENT .............................................................................. 120 
12.4. PATIENT CONFIDENTIALITY ............................................................................................... 120 
12.5. DEFINITION OF THE END OF THE RESEARCH ...................................................................... 121 
13. 
FINANCING AND INSURANCE .............................................................................................. 122 
13.1. FINANCIAL ISSUES ............................................................................................................. 122 
13.2. INSURANCE AND PATIENT INJURY ...................................................................................... 122 
14. 
STUDY RESULTS AND PUBLICATION POLICY ....................................................................... 123 
14.1. STUDY REPORT .................................................................................................................. 123 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION .................................................................................................................... 123 
15. 
REFERENCES LIST .............................................................................................................. 125 
APPENDICES .................................................................................................................................... 128 
APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ....................................... 129 
APPENDIX II: ADEQUATE DIET AND LIFESTYLE RECOMMENDATIONS ................................................. 137 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ................................................................ 138 


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APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................... 140 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .................................................................. 141 
 
 


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 TABLE OF TABLES 
Table 1: 
STUDY GENERAL ASSESSMENT SCHEDULE .......................................................................... 21 
Table 2: 
STUDY BIOLOGICAL ASSESSMENT SCHEDULE ..................................................................... 25 
Table 3: 
Recommended values for fibrosis staging ............................................................................ 84 
Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) by system 
organ class reported in completed elafibranor clinical studies with repeated administration of 
elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum tolerated dose) ......... 88 
 


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 TABLE OF FIGURES 
Figure 1: STUDY DURATION AND VISIT SCHEDULE 
28 
Figure 2: PREGNANCY TESTING SCHEDULE FOR WOMEN OF CHILDBEARING POTENTIAL 
29 
 


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LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
Albumin-creatinine ratio 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoAI 
apolipoprotein AI 
ApoAII 
apolipoprotein AII 
ApoB 
apolipoprotein B 
ApoCIII 
apolipoprotein CIII 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Bx 
biological assessment visit 
CA 
competent authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EES 
efficacy evaluable sample 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FFA 
free fatty acid 
FIB-4 
fibrosis 4 score 
FLI 
fatty liver index 
FPFV 
first patient first visit 
FSS 
Full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP1 
glucagon-like peptide 1 


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HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostasis model assessment of insulin resistance 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
HSC 
hepatic stellate cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IR 
insulin resistance 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LPLV 
last patient last visit 
 
 
M2 
anti-inflammatory macrophages 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model end stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PT 
prothrombin time 
PUFA 
polyunsaturated fatty acids 
QD 
once daily 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAF 
steatosis, activity, and fibrosis 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SF-36 
36-Item Short-Form Health Survey 
SGLT2  
sodium/glucose cotransporter 2 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SVx 
Screening Visit x 
TLC 
therapeutic lifestyle change 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
1.1. 
NONALCOHOLIC STEATOHEPATITIS 
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by excessive fat 
accumulation in the liver (steatosis). Nonalcoholic steatohepatitis (NASH) defines a subgroup of NAFLD 
where steatosis coexists with hepatocyte injury and inflammation (steatohepatitis), with or without fibrosis. 
Nonalcoholic steatohepatitis is considered by the European Association for the Study of the Liver (EASL) 
and the American Association for the Study of Liver Diseases (AASLD) as an increasing public health issue 
owing to its close epidemiological association with the worldwide epidemic of obesity and type 2 diabetes. 
The prevalence of NAFLD in the general population assessed by ultrasonography is 20% to 30% in Europe. 
A similar prevalence of 15% to 25% was documented histologically by postmortem studies. A high 
prevalence of histological NAFLD has been described in apparently healthy liver donors: 12% to 18% in 
Europe and 27% to 38% in the US. Furthermore, with a sensitive technique such as magnetic resonance 
spectroscopy, 34% have NAFLD. 
Interestingly, 39% of newly diagnosed cases of chronic liver disease had NAFLD, making NASH one of the 
top causes of liver diseases in Western countries. Using the histological definition of NASH, recent studies 
have shown a high prevalence of NASH among NAFLD cases: 43% to 55% in patients with increased 
aminotransferases, 49% in morbidly obese patients, and 67% in a subset of patients with incident chronic 
liver disease. Finally, in apparently healthy liver donors the prevalence of NASH ranges from 3% to 16% in 
Europe and from 6% to 15% in the US. 
The commonest cause of NASH is primary NAFLD-associated insulin resistance and its phenotypic 
manifestations, namely excess weight/obesity, visceral obesity, type 2 diabetes, hypertriglyceridemia, and 
arterial hypertension. A causal association has been suggested by longitudinal studies showing a 
chronological association between the progression of insulin resistance, the metabolic syndrome and the 
occurrence of NAFLD/NASH. 
1.2. 
PATHOPHYSIOLOGICAL PROCESS OF NONALCOHOLIC STEATOHEPATITIS 
A widely described model suggests that the development of NAFLD into NASH requires several ‘hits’ or 
insults.1,2 According to this model, increased hepatic levels of free fatty acid (FFA) consequent to impaired 
insulin sensitivity in the liver and peripheral tissues may serve as the first hit. The increased hepatocyte 
FFA load would further increase insulin resistance (IR), steatosis, oxidative stress with lipid peroxidation, 
endoplasmic reticulum stress, resulting in inflammatory cell accumulation and activation into the liver 
(second hit). This finally leads to hepatocyte growth arrest or apoptosis, which activates hepatic progenitor 
cells and associated bile ductular proliferations, cells that initiate inadequate repair by producing a diverse 
range and high concentrations of profibrogenic cytokines and growth factors that activate hepatic stellate 


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cells (HSC) and perivascular or portal fibroblasts. The activated HSC themselves can release chemotactic 
factors that recruit inflammatory cells, creating a deleterious feedback inflammatory loop’ that leads to 
fibrogenesis. Collagen and other extracellular matrix components accumulate within the liver, which may 
result in distortion of the hepatic architecture and finally cirrhosis. Thus, in this “multiple-hit” model IR can 
be considered as the first step on the pathogenic road leading to NASH, fibrosis and cirrhosis. 
However, this “multiple-hit” model has been recently challenged by data suggesting that mechanisms that 
can drive disease progression can also induce steatosis. Oxidative stress and gut flora/cytokines can induce 
steatosis as well as necroinflammation and fibrosis. Free fatty acids can initiate hepatocyte apoptosis in 
addition to being esterified to triglycerides. Endoplasmic stress can also lead to steatosis, oxidative stress, 
and apoptosis. Since all these mechanisms are important in obesity and IR, it would seem likely that they 
are the true “first hits” leading to increased hepatic FFA flux and oxidative-, endoplasmic reticulum-, and 
cytokine-mediated stress that result in both steatosis and progressive liver damage. Steatosis should 
therefore be considered part of the liver’s early “adaptive” response to stress, rather than a first hit in 
disease progression. Accordingly, while in some situations its severity may act as a biomarker of ongoing 
injurious and fibrotic mechanisms resulting in disease progression, it should not be considered a sole 
therapeutic target. Instead attention should be paid on the mechanisms of cellular injury and fibrosis – the 
“second hits.” 
Oxidized by-products are harmful adducts that can cause liver injury, resulting in subsequent fibrosis.3 Lipid 
peroxidation and oxidative stress up-regulate liver fibrosis via activation of stellate cells and increased 
production of Transforming Growth Factor-beta.4 Over expression of uncoupling proteins has been 
associated with a reduction in generation of reactive oxygen species and Kupffer cell activation, which 
might attenuate injury in NAFLD. In addition to insulin resistance, several authors have shown that leptin 
contributes to an insulin-resistant state and might even stimulate fibrogenesis in animal models of NAFLD.5 
Inflammatory mediators have been implicated in the progression of NAFLD and are the focus for new 
therapeutics. Pro-inflammatory transcription factors such as Nuclear Factor kappa B (NF-κB) are often 
elevated in patients with NASH.6 Tumor Necrosis Factor-alpha (TNFα) is another inflammatory mediator 
largely produced by macrophages, but also by other cells including adipocytes and hepatocytes. Elevated 
levels of TNFα have been detected in obese patients with insulin resistance and NASH. The TNFα-mediated 
hepatic injury results from the inhibition of mitochondrial electron transport and release of reactive oxygen 
species that stimulate lipid peroxidation. On another hand, adiponectin decreases fatty acid oxidation and 
inhibits hepatic gluconeogenesis.7 Both human and mouse models have demonstrated that lower 
adiponectin levels are associated with increased severity of hepatic inflammation.8,9 The TNFα is an 
inflammatory mediator largely produced by macrophages, but also elaborated by other cells including 
adipocytes and hepatocytes.1,10 Elevated levels of TNFα have been detected in obese patients with insulin 
resistance and NASH.11,12 TNFα-mediated hepatic injury results from inhibition of mitochondrial electron 
transport and release of reactive oxygen species that stimulate lipid peroxidation.10 


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Recently, scientists have focused on the role of Kupffer cells in the pathogenesis of NAFLD. Kupffer cells 
are the resident macrophages of the liver and function in both innate and adaptive immunity as active 
phagocytosing agents and antigen-presenting cells (via toll-like receptors) to T-cells. Finally, the 
proapoptotic gene Bax is upregulated in patients with NASH and alcoholic liver disease.13 Additionally, 
caspase levels, by-products of cellular apoptosis, are also increased in these groups of patients. 
1.3. 
ELAFIBRANOR: RATIONALE FOR A MIXED PPAR ALPHA/DELTA AGONIST IN NASH 
The GENFIT drug candidate, elafibranor, and its main active circulating metabolite, GFT1007, are dual 
peroxisome proliferator-activated receptor (PPAR)α/δ modulators with preferential activity on PPARα over 
PPARδ (about fivefold more potent on human PPAR [hPPAR]α than on hPPARδ). The PPARδ properties of 
elafibranor and GFT1007 have been demonstrated in both human skeletal muscle cells (a pure PPARδ 
response) and human hepatocytes (a mixed PPARα/δ response). 
The PPARα receptors are most prominently expressed in the liver and can be activated by drugs of the 
fibrate class. Activation results in increased uptake and oxidation of FFAs, increased triglyceride hydrolysis 
and upregluation of apolipoprotein (Apo)A-I and ApoA-II. The net effect is fatty acid oxidation, decrease in 
serum triglycerides, a rise in high-density lipoprotein cholesterol (HDL-C) levels, and an increase in 
cholesterol efflux. The PPARα activation has also anti-inflammatory effects via inhibition of COX2, IL-6, and 
C-reactive protein (CRP). Some PPARα compounds have proved their effectiveness in animal models like 
Methionine-Choline-Deficient diet model or CCl4 in reducing the steatosis. However, clinical trials with 
fibrates in human NASH have been unimpressive. For example in a pilot study, 12 months treatment with 
clofibrate in 16 patients with NASH and elevated triglycerides had no impact on liver enzyme elevation or 
triglycerides levels.14 
The PPARδ appears to be a powerful metabolic regulator, with actions on fat, skeletal muscle, liver, and 
heart. Its activation enhances fatty acid transport and oxidation, improves glucose homeostasis via 
improved insulin sensitivity and inhibition of hepatic glucose output, turns off macrophage inflammatory 
responses, and dramatically increases circulating HDL-C levels. Thus selective PPARδ agonists have the 
potential to target multiple components of the metabolic syndrome, including obesity, dyslipidemia, 
hypertriglyceridemia insulin resistance, and probably NASH. 
Accordingly, PPARδ ligands also show promise in chronic inflammatory models of hepatotoxicity.15 Notably, 
biomarkers of liver toxicity, including serum alanine aminotransferase (ALT), hepatic TNFα, TNF-like weak 
inducer of apoptosis receptor, were all higher in carbon tetrachloride-treated PPARδ knockout mice 
compared to wild-type mice. GW0742 reduced serum ALT, TNFα, S100A6, MCP1, and TNF-like weak 
inducer of apoptosis receptor in wild-type mice, but not PPARδ knockouts. 
Finally, in a short clinical trial, a pure PPARδ agonist, GW501516, has demonstrated efficacy on liver fat 
content while improving insulin resistance and decreasing γGT.16 


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Considering the emerging role of Kupffer cells in the pathogenesis, 2 recent publications identified PPARδ 
as a crucial signaling receptor controlling the phenotypic switch between classical pro-inflammatory and 
alternative anti-inflammatory (M2) macrophages.17,18 These studies demonstrate that PPARδ encourages 
macrophages toward the alternative M2 phenotype, which improves fatty acid metabolism, insulin 
sensitivity, and suppresses inflammation. The finding raise the possibility that small molecule agonist of 
PPARδ may be effective therapeutic targets for the treatment of chronic inflammation in the liver. 
The match between the activation of PPARα and PPARδ in the liver may thus improve NASH. Accordingly, 
in several well-established experimental models of NAFLD/NASH and liver fibrosis, treatment with 
elafibranor confers liver protection both in preventive and therapeutic approaches on established 
pathologies. These effects have been demonstrated through plasma and hepatic markers, as well as liver 
macro- and micro- histological examination. These studies have shown that elafibranor acts on several 
mechanisms involved in NASH pathogenesis: steatosis, inflammation, and fibrosis pathways. 
Complementary studies have demonstrated that both PPARα-dependent and PPARα-independent 
mechanisms participate in the beneficial effects of elafibranor on NAFLD/NASH. 
1.4. 
SUMMARY OF NONCLINICAL STUDIES 
1.4.1. 
Pharmacology 
In several well-recognized experimental models of NAFLD/NASH, treatment with elafibranor confers liver 
protection both in preventive and therapeutic approaches on established pathologies. These effects have 
been demonstrated through plasma and hepatic markers, as well as liver macro- and micro-histological 
examination. These studies have shown that elafibranor acts on several mechanisms involved in NASH 
pathogenesis: steatosis, inflammation, and fibrosis pathways. Complementary studies have demonstrated 
that both PPAR-dependent and PPAR-independent mechanisms participate in the beneficial effects of 
elafibranor on experimental NAFLD/NASH. 
Besides hepatoprotection, the efficacy of elafibranor has been assessed in numerous pharmacological 
preclinical models of metabolic disorders. 
Briefly, in experimental models of type 2 diabetes, elafibranor has insulin-sensitizing and glucose lowering 
properties. In db/db mice, a 28-day treatment with elafibranor produced a dose-dependent decrease in 
fasting plasma glucose and glycated hemoglobin (HbA1c), comparable to the effect of rosiglitazone. 
However, in contrast to the PPARγ reference agonist, elafibranor did not increase plasma adiponectin, thus 
ruling out a PPARγ -mediated effect on adipose tissues. Similarly, in ob/ob mice, elafibranor ameliorated 
plasma glucose and insulin levels without modulating plasma adiponectin or inducing PPAR target genes in 
adipose tissues. 
Besides its effects on NAFLD/NASH and type 2 diabetes, oral treatment with elafibranor in a mouse model 
of dyslipidemia potently reduced plasma triglycerides and total cholesterol through the induction of PPARα 


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target genes in the liver and by reduction of ApoCIII gene expression. In parallel, elafibranor increased 
plasma HDL-C levels more potently than the PPARα reference compound fenofibrate. The chronic 
treatment of these mice fed a high fat diet with elafibranor prevented the development of atherosclerotic 
plaques in the aorta. 
1.4.2. 
Safety pharmacology 
Any potential effect on the cardiovascular, respiratory, and central nervous system has been assessed and 
no safety issue was identified. 
1.4.3. 
Absorption/distribution/metabolism/excretion studies (ADME) 
In animal studies, elafibranor was well and rapidly absorbed although absolute bioavailability was 
moderate (about 20% to 40%). Elafibranor is extensively metabolized and the activity is mainly carried by 
the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure for both 
elafibranor and GFT1007 linearly increase with the dose after single or repeated administrations. 
Elafibranor and its metabolites are rapidly cleared from the plasma and they are totally excreted by both 
fecal and renal route within 48 hours. In the rat elafibranor and/or its metabolites are rapidly excreted into 
the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of elafibranor 
and/or GFT1007. The distribution study in the rat supports the liver targeting of elafibranor and/or its 
metabolites. 
In vitro elafibranor does not inhibit cytochrome p450 (CYP)1A2, CYP3A4, and CYP2D6 with moderate 
inhibition of CYP2C9 and weak inhibition of CYP2C8, CYP2C19, and CYP4A11. GFT1007 does not produce 
any inhibition of the CYP450 isoforms 1A2, 3A4, 2C19, and 2D6, and only weak inhibition of CYP2C8 and 
CYP2C9. Both molecules also show weak inhibition of CYP3A4/5, but only with midazolam as substrate. 
Thus, the risk of drug-drug interaction due to an inhibition of the main cytochromes involved in drug 
metabolism should be limited. Potential interaction with CYP2C9 metabolized drugs has been assessed 
through a clinical study (GFT505-112-8) designed to evaluate potential pharmacokinetic (PK) interaction of 
elafibranor 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that elafibranor administration did not affect the PK profile of warfarin (R-warfarin and S-
warfarin). 
A protein binding study showed that elafibranor and GFT1007 were highly bound to human serum albumin. 
The risk of drug-drug interaction due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether elafibranor (GFT505) and it principal 
metabolite GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the 
potential for drug-drug interaction (DDI). Based on the results of the OATP1B3 transporter inhibition assay, 


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elafibranor (GFT505), has recently been assessed in a follow-up clinical DDI study with the 
OATP1B3-sensitive substrate, atorvastatin. 
For the other drug transporters studied, the interaction observed does not require follow-up studies based 
on current regulatory guidance. 
The metabolic stability and metabolism pathways of elafibranor (GFT505) have been studied on liver 
microsomes and in primary hepatocytes from rat, dog, mouse, monkey, and human. There was no 
evidence of the formation of unique human metabolites or metabolites formed at disproportionately higher 
levels in human hepatocytes than in any other species. 
An in vivo study has been performed to compare the bioavailability of 14C-GFT505 in the rat, dog, minipig 
and monkey. This study showed that in all species 14C-GFT505 is rapidly absorbed, although absolute 
bioavailability was moderate (about 20% to 40%). 
1.4.4. 
Toxicology 
1.4.4.1. 
Mutagenicity and genotoxicity 
The toxicology program performed according to International Council for Harmonisation (ICH) guidelines 
demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.4.4.2. 
Acute toxicity 
According to acute toxicity studies results, it can be concluded that elafibranor is extremely safe when 
administered as single oral doses in rat and mouse, since no sign of toxicity was detected up to the dose of 
1000 mg/kg. 
1.4.4.3. 
Repeated dose toxicity studies 
The safety of elafibranor has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPARα-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly sensitive 
to PPARα agonist induced peroxisome proliferation and associated liver side effects. Thus, available 
information on this class of drug which includes marketed fibrates together with the lack of any liver side 
effects in monkeys treated with high doses of elafibranor for 1 year support the nonrelevance to human.19 
Overall, these studies did not reveal any other safety issues up to the highest doses tested. Notably, 
elafibranor did not have any of the known PPARγ-related concerns such as excess in weight gain, 
hemodilution, edema, cardiomegaly, adiponectin induction, or urinary bladder carcinoma. 


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1.4.4.4. 
Phototoxicity studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 NRU phototoxicity test and 
the UV-Local Lymph Node Assay (LLNA) test in mice. Elafibranor (GFT505), but not its major metabolite 
GFT1007, showed UVA-dependent cytotoxicity in vitro. The UV-LLNA test was performed in mice with oral 
dosing for 3 days at up to 800 mg/kg/day elafibranor. Although a very conservative no observed effect 
level (NOAEL) was set at 400 mg/kg/day based on isolated findings at the highest dose, it is considered 
that data are more in favor of an absence of phototoxic effect, given the tissue distribution of elafibranor 
(GFT505), and absence of phototoxicity signal in the clinical studies. 
1.5. 
CLINICAL STUDIES 
1.5.1. 
Phase I program 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, one of them ongoing. A total of 608 volunteers were randomized in 
these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
The plasma concentrations of elafibranor and GFT1007 were determined using validated high-performance 
liquid chromatography tandem mass spectrometry methods. The PK parameters were calculated using a 
noncompartmental analysis. 
In healthy volunteers, the PK of elafibranor and GFT1007 after single administration of elafibranor at rising 
dose levels were assessed in 2 distinct double-blind, placebo-controlled randomized trials from 10 to 
120 mg (GFT505-106-1 and GFT505-108-4). The PK of elafibranor and GFT1007 after repeated doses of 
elafibranor at rising dose levels were assessed in 3 distinct double-blind, placebo-controlled randomized 
trials: GFT505-106-2 (5, 10, 20, and 30 mg/d), GFT505-108-4 (40, 60, 80, and 100 mg/d) and 
GFT505-113-9 (300 and 360 mg/d). 
In overweight/obese but otherwise healthy volunteers, the PK of elafibranor and GFT1007 after single 
administration of elafibranor at rising dose levels from 180 to 300 mg were assessed in a double-blind, 
placebo-controlled randomized trial (GFT505-111-7). In the same trial, the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at dose levels from 120 to 240 mg, were assessed in overweight/obese 
but otherwise healthy volunteers. Another part of this trial assessed the PK of elafibranor and GFT1007 
after repeated doses of elafibranor at 180 mg in type 2 diabetic patients. 
The food effect on PK of elafibranor and GFT1007 was assessed in healthy volunteers at the dose of 30 mg 
elafibranor in a Phase I, randomized, crossover trial (GFT505-106-1). 
The PK of elafibranor and GFT1007 obtained after administration of the different formulations used 
throughout clinical evaluation of elafibranor were compared in dedicated clinical trials in healthy 


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volunteers: GFT505-108-3, GFT505-111-7, and GFT505-115-12. Comparable relative bioavailability was 
demonstrated. 
The lack of PK DDI between elafibranor (80 mg/d) and Simvastatin has been verified (GFT505-109-5). 
The lack of effect of a concomitant administration of sitagliptin on elafibranor PK has been verified 
(GFT505-109-6). 
The lack of effect of elafibranor administration (120 mg/d) on the PK and pharmacodynamics (PD) of 
warfarin has been verified (GFT505-112-8). 
The lack of effect of elafibranor administration (180 mg/d) on the PK and PD of atorvastatin has been 
verified (GFT505-115-11). 
The study GFT505-113-9 evaluated the effect of multiple oral doses of elafibranor on the QT/corrected QT 
(QTc) interval compared to placebo with moxifloxacin (400 mg in single oral dose) as a positive control, in 
healthy male and female volunteers. No effect of elafibranor on QT/QTc interval at both therapeutic and 
supratherapeutic doses for 14 days was observed. 
The excretion balance of radiocarbon (i.e., the sum of 14C-labeled elafibranor and its 14C-labeled 
metabolites) and the metabolite profiling and PK of elafibranor after a single oral dose of 120 mg 
14C-labeled elafibranor have been assessed (GFT505-114-10). Most of the radiocarbon was excreted in 
feces (77.1%) and urine (19.3%), giving a recovery of 96.3% of the administered dose. The metabolite 
profile was assessed in plasma, urine, and feces, and did not highlight any new Phase I metabolite but 
allowed the identification of new glucuronated metabolites, one of them being the main urinary metabolite 
(12% of the administered dose). 
Part of the study GFT505-115-12 is still ongoing. The objective is to assess the dose linearity after single 
oral administration of 120, 180 and 240 mg of elafibranor, and if confirmed, to assess the time dependency 
of the PK parameters after single and multiple oral administration of therapeutic dose of elafibranor. 
1.5.2. 
Phase II program 
A Phase II program was initiated to assess the safety, and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed (Clinical Study Report [CSR] 
not yet available), and evaluated the efficacy and safety of elafibranor 80 mg and 120 mg on 
steatohepatitis in 274 patients with NASH. 
A Phase IIa pilot study (GFT505-207-1) was first conducted to evaluate the efficacy, safety, and tolerability 
of elafibranor at 30 mg/d for 28 days in patients with Fredrickson type IIb dyslipidemia. Thirty-seven 
randomized patients received elafibranor 30 mg (24 patients) or placebo (13 patients) over a 28-day 


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treatment period. Although improvements were observed on primary lipid parameters, these trends were 
not statistically significant versus placebo. 
The Phase IIa study (GFT505-208-3) assessed efficacy and safety in men and postmenopausal women 
with atherogenic dyslipidemia (high triglycerides, low HDL-C) and abdominal obesity treated once a day for 
28 days with 80 mg/d of elafibranor. Ninety-four patients were randomized: 63 patients in the elafibranor 
80 mg/d arm and 31 patients in the placebo arm. 
The Phase IIa study (GFT505-209-4) assessed efficacy and safety in patients treated for 35 days with 
elafibranor at 80 mg/d. This study targeted patients with impaired fasting glucose and impaired glucose 
tolerance associated with abdominal obesity. Forty-seven patients were randomized: 23 patients in the 
elafibranor 80 mg/d arm and 24 patients in the placebo arm. 
The Phase IIa study GFT505-210-5 assessed efficacy and safety in patients with type 2 diabetes mellitus. 
Patients were treated once a day for 12 weeks with 80 mg/d of elafibranor. Ninety-seven patients were 
randomized: 50 patients in the elafibranor 80 mg/d arm and 47 patients in the placebo arm. 
The Phase IIa study (GFT505-210-6) was designed to evaluate the safety and efficacy of elafibranor on 
hepatic and peripheral insulin sensitivity using the gold standard glucose clamp technique in male patients 
with homeostasis model assessment of insulin resistance (HOMA-IR) >3 and abdominal obesity. Patients 
were treated once daily (QD) with 80 mg/d of elafibranor or placebo for 8 weeks in a crossover design. In 
this study, after 8 weeks of treatment, elafibranor significantly improved the response of the liver to insulin 
action. Indeed, at the first level of insulin perfusion, the insulin-induced decrease in hepatic glucose 
production was -49±4% after elafibranor versus -34±4% after placebo (p=0.0016). The insulin sensitivity 
of the muscles and other peripheral tissues measured at the second level of insulin perfusion was also 
increased by 28% with a significant effect on the glucose infusion rate (3.69±0.31 mg/kg/min after 
elafibranor versus 3.21±0.31 mg/kg/min after placebo, p=0.048). Moreover, at the end of the treatment 
period, elafibranor significantly lowered the FFA levels measured at the first insulin level (FFA 0.21 mEq/L 
after elafibranor versus 0.27 mEq/L after placebo, p=0.006). 
The favorable effect of elafibranor on insulin sensitivity and glucose homeostasis was also observed in 
studies GFT505-209-4 and GFT505-210-5. In prediabetic patients with impaired fasting glucose, impaired 
glucose tolerance, and abdominal obesity (study GFT505-209-4), treatment with elafibranor 80 mg/d for 
28 days led to a significant decrease in fasting plasma glucose (-5%, p=0.04), fasting plasma insulin 
(-25%, p=0.009), and consequently improvement of the insulin resistance index (HOMA-IR: -31%, 
p=0.027). In diabetic patients treated for 3 months with 80 mg/d of elafibranor (study GFT505-210-5), 
oral glucose tolerance test-derived parameters, including area under the time-concentration curve for 
glycemia, insulinemia and FFA levels, significantly improved. 
In all Phase IIa studies, patients treated with elafibranor at 80 mg/d for 1 to 3 months consistently 
experienced an improvement of the plasma lipid profile, with significant reduction of triglycerides 


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(-20% to -35%), reduction in low-density lipoprotein cholesterol (LDL-C) (-10% to -15% in prediabetic, 
insulin-resistant and diabetic patients) and increase in HDL-C (+10% in patients with atherogenic 
dyslipidemia). In addition, elafibranor treatment consistently increased the anti-atherogenic apolipoproteins 
(ApoAI and ApoAII) while reducing the pro-atherogenic apolipoproteins (ApoB, ApoCIII, ApoE). 
In all Phase IIa studies, elafibranor treatment at 80 mg/d for 1 to 3 months also led to favorable 
reductions in inflammatory markers. Reduced haptoglobin levels were observed in all Phase IIa clinical 
trials with elafibranor, with the greatest effect obtained after 3 months of treatment in diabetic patients 
(-20% in the elafibranor group versus +6% in the placebo group, p<0.001). Similarly, fibrinogen levels 
were consistently decreased by approximately 10% in all Phase IIa clinical trials with elafibranor, and 
high-sensitivity CRP levels were lowered after 3 months of treatment in diabetic patients (-17% in the 
elafibranor group versus +52% in the placebo group). 
Finally, beneficial effects of elafibranor on liver function were consistently observed in all Phase IIa clinical 
trials of patients treated for 1 to 3 months with 80 mg/d elafibranor. Significant reductions in circulating 
levels of gamma-glutamyl transferase (GGT) were observed in each study and reached up to -29% in 
elafibranor treated groups compared to placebo. In addition, in insulin-resistant patients, elafibranor 
treatment induced a significant reduction in ALT (-20% compared to placebo), while the level of aspartate 
aminotransferase (AST) was unchanged. 
A Phase IIb study in NASH patients (GFT505-212-7) included 274 patients and involved a total of 
56 centers in the US and in multiple European countries (France, Belgium, The Netherlands, Italy, UK, 
Germany, Spain, and Romania). The study evaluated the efficacy and safety of elafibranor at 80 and 
120 mg QD for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of 
fibrosis. 
The study analyses showed that elafibranor at 120 mg demonstrates efficacy on the resolution of NASH 
without worsening of fibrosis in patients with an active disease (NAFLD Activity Score [NAS] score ≥4). 
Importantly, elafibranor at 120 mg concomitantly improved the cardiometabolic risk profile of NASH 
patients by decreasing plasma triglycerides, total and LDL-C, increasing HDL-C and improving 
inflammation, insulin resistance and glucose homeostasis. 
The good safety profile of elafibranor was confirmed in this study. Elafibranor was well tolerated, at both 
doses. From the start to end of the study, regular safety reviews did not generate any comment or 
additional request from the Data Safety Monitoring Board (DSMB). The most frequent and expected 
adverse events were of gastrointestinal nature. Clinical adverse events were generally mild to moderate in 
severity and were similar in the placebo and treated groups for the most frequently reported treatment-
related AEs. Leukocyturia, hypoglycemia and diabetes mellitus inadequate control were more frequent in 
elafibranor arms as well as cutaneous rash, arthralgia, decrease in appetite, dizziness and renal impairment 
which were only reported in the elafibranor treated groups. Serious adverse events (SAE) were reported in 
27 patients treated with elafibranor (13 with elafibranor 80 mg/d and 14 with elafibranor 120 mg/d). Of 


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these, only 6 SAEs reported in 4 patients treated with elafibranor were considered as related to treatment. 
Nineteen patients discontinued the study for safety reason with no imbalance between groups (6 in the 
placebo arm, 6 in the elafibranor 80 mg arm, and 7 in the elafibranor 120 mg arm). 
1.6. 
CONCLUSION 
Clinical data confirmed the beneficial effect of elafibranor in NASH patients, with efficacy on histology 
associated with improvement on insulin resistance, and with relevant reductions in markers of liver injury 
such as GGT and ALT, and in inflammatory markers. It demonstrated also improvement in lipid profile 
resulting in a beneficial balance between pro and anti-atherogenic markers. Moreover, it highlighted the 
good safety profile of elafibranor, since no major safety concerns were raised during these studies. 
For additional information see Investigator’s Brochure. 
1.7. 
RATIONALE FOR STUDY POPULATION 
Given the natural fluctuation of the disease for patients with mild NASH (NAS score of 3), Phase IIb study 
results have clearly highlighted that only NASH patients with moderate to severe disease (NAS score≥4) 
should be treated. 
Regarding fibrosis, available data from meta-analyses demonstrate that NASH patients are at greatest risk 
of progression to advanced fibrosis, cirrhosis and liver outcomes. Patients with NASH develop progressive 
fibrosis in 25% to 50% of individuals over 4-6 years, while 15% to 25% of individuals with NASH can 
progress to cirrhosis.20 In another study, with a mean follow-up of 13 years, 13.3% of NASH patients with 
mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 at inclusion developed 
cirrhosis.21 
Considering these data, it is reasonable to include NASH patients with any stage of fibrosis (stage 1 to 3) in 
the Phase III program, from both safety and prospect for benefit standpoints. However, since in patients 
with NASH and advanced fibrosis (F2-F3) the probability of developing cirrhosis is much higher than in 
patients with early fibrosis (F1), the population evaluated for the long-term outcome needs to be based on 
the advanced fibrosis patients in order to enhance the chances of demonstrating a benefit within a 
reasonable timeframe. 
Accordingly, the target population for the analysis of surrogate endpoint and liver outcomes will be NASH 
patients with advanced fibrosis (F2-F3). The enrollment of patients with advanced fibrosis for the 
evaluation of long-term outcomes including progression to cirrhosis should ensure that an expected 
number of events, calculated based on progression rate for each fibrosis stage, are obtained. Based on the 
literature, 21,22,23,24,25 in patients with NASH and advanced fibrosis (F2-F3) this progression rate can be 
estimated at 8% per year for fibrosis stage 3 and 6% per year for fibrosis stage 2, thus an average of 7% 
for advanced fibrosis. 


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As a conservative approach, no supplementary percentage was added to the estimated progression rate to 
histological cirrhosis (7%) for all the other events of the composite endpoint not linked to cirrhosis. 
Generally, liver decompensation events occur only when cirrhosis is present and the progression rate to the 
other events is expected to be very low. 
A limited number of NASH patients with fibrosis stage 1 and associated comorbidities known to be at risk 
of fast disease progression will be included in the study as an exploratory group. 
Enrollment of female patients will be capped at 40% in each group for this study to mirror the higher 
prevalence of NASH in males compared to females.26 
1.8. 
JUSTIFICATION OF THE SELECTED DOSE 
The results obtained in the Phase IIb study evaluating the resolution of NASH clearly demonstrated the 
superiority of the elafibranor dose of 120 mg over 80 mg on the histological endpoint, regardless of the 
population selected (Intent-To-Treat [ITT] or Full Analysis Set) or the subgroup tested, indicating that the 
dose to be used for the Phase III trial should be 120 mg. 
To support this assumption, a dose-response modeling was performed based on data obtained in the 
Phase I clinical program with 14-day repeated dose studies ranging from 5 mg to 360 mg daily dose. In 
this model, the studied response was the change at endpoint versus baseline in biochemical parameters 
known to be associated in a dose-dependent manner with elafibranor exposure, such as liver enzymes 
(ALT, GGT, alkaline phosphatase), plasma lipids (triglycerides, LDL-C, HDL-C) or serum creatinine. Based 
on this modeling, the optimum dose was consistently assessed as a value of 118 mg. Therefore, given its 
good safety profile and evidence of efficacy, both supported by the dose-response modeling, 120 mg 
elafibranor appears to be the most appropriate dose for the upcoming Phase III trial. 
1.9. 
RATIONALE FOR EFFICACY ENDPOINT 
1.9.1. 
Primary endpoint for application under conditional approval 
Steatohepatitis is indirectly associated with reduced hepatic survival in NAFLD.21,27 It drives fibrogenesis, a 
slow process of hepatic scar formation that can result in cirrhosis and its deadly complications such as liver 
failure, portal hypertension, and hepatocellular carcinoma. Consequently, clearance of steatohepatitis,28 
i.e., reversal to a normal liver or to steatosis without steatohepatitis – a condition not associated with 
increased hepatic morbidity or mortality – is expected to improve hepatic prognosis. Natural history studies 
are now available showing that patients with steatohepatitis but not those with steatosis only (i.e., 
nonNASH NAFLD) are the ones that progress to cirrhosis and liver-related outcomes. This forms the basis 
for "resolution of NASH" as a desirable outcome of therapy in the short-term; a concept widely embraced 
by the academic community and expressed in several scientific society endorsed position papers.29,30 Based 
on the recently published recommendations from this workshop,30 resolution of NASH with no worsening of 
fibrosis may be an acceptable surrogate endpoint suitable for a Phase III enrolling patients with NASH and 


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fibrosis. Based on recent data that have shown that fibrosis stage of 2 or more is related to liver-related 
mortality,22 the “no worsening of fibrosis” should be no progression of one stage in fibrosis. 
1.9.2. 
Primary endpoint for clinical outcome (postapproval confirmation) 
The primary endpoint of the Long-term Treatment Period of the study is to evaluate the effect of 
elafibranor on all-cause mortality and liver-related clinical outcomes as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint). 
Primary endpoint events include overall mortality, progression to cirrhosis, and the full list of portal 
hypertension/cirrhosis related events (liver transplantation, model end stage liver disease (MELD) score 
≥15, hepatocellular carcinoma (HCC), and hospitalization due to occurrence of hepatic encephalopathy, 
variceal bleeding, spontaneous bacterial peritonitis, uncontrolled ascites, hepatorenal syndrome, 
hepatopulmonary syndrome, and chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
[provided that these lead to hospitalization or transfusion]). 
Singh et al. recently provided a thorough meta-analysis of paired biopsy studies to obtain the most 
accurate estimate of the fibrosis progression rate in a large cohort of patients with NAFLD.25 Over 
2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, 
and 22.3% had an improvement in fibrosis stage. Overall, the annual fibrosis progression rate in a 
population of patients with NAFLD who had stage 0 fibrosis at baseline was 0.07 stage/year compared to 
0.14 stage/year in a population of patients with NASH. In another study of 108 patients, no significant 
difference in the proportion exhibiting fibrosis progression was found between those with NAFLD or 
NASH.31 In the whole cohort, the mean annual rate of fibrosis progression was 0.08 stage/year. 
Based on the literature, in patients with NASH and advanced fibrosis (F2-F3), the probability of developing 
cirrhosis can be estimated at 8% per year for fibrosis F3 and 6% per year for fibrosis F2.21,22,23,24,25 
In conclusion, the difference in progression to cirrhosis, other liver-related events, and total deaths 
between treatment and control groups can be considered as a potential clinically meaningful outcome 
measure for clinical trials. This long-term outcome including progression to cirrhosis is considered 
acceptable,30 and required in a postapproval study for treatments approved under conditional approval. 
1.10. RATIONALE FOR STUDY DURATION 
In accordance with the AASLD and EASL recommendations, 72-weeks of treatment have been defined for 
the first stage of the study in order to demonstrate the efficacy of elafibranor on resolution of NASH 
without worsening of fibrosis. 
The estimated duration of the Long-term Treatment Period is based on a 7% probability of patients with 
NASH and moderate and advanced fibrosis (F2-F3) developing cirrhosis or other liver-related events as 


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determined from recently published data 21,22,23,24,25 and the available data of the mortality risk in this 
patient population.32,33 
1.11. RATIONALE FOR SAFETY MONITORING 
The safety of use of the dose of 120 mg/d of elafibranor during the proposed trial is supported by the 
chronic toxicity studies and previous Phase I and Phase II trials. Indeed, the toxicology package of 
elafibranor does not reveal any major safety concern, based on the conclusion that elafibranor-induced 
liver toxicity in rodents is not relevant to nonprimates (no evidence of liver toxicity in monkeys after 1 year 
but improvement of liver function markers) and humans (consistent improvement of liver function markers 
in all Phase II trials). These toxicology results and conclusions are on-line with the extensive literature on 
the liver effects of PPAR agonists. 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review (as defined by the DSMB Charter) on a regular basis during the trial to protect patient 
welfare and preserve study integrity. 
Knowing the risks associated with NASH and disease progression, specific attention will be paid to potential 
hepatotoxicity, liver-related and cardiovascular events. 
Given the known effect of elafibranor on serum creatinine increase, special attention will be paid to all the 
renal safety markers (plasmatic or urinary parameters), including but not limited to albumin-creatinine 
ratio, cystatin C, neutrophil gelatinase-associated lipocalin (N-Gal), N acetyl β D-glucosaminidase β-NAG, 
kidney injury molecule-1 (KIM-1). Serum creatinine and creatinine clearance, and results of urinalysis 
(dipstick) will be reported at each visit, as well as blood urea nitrogen. The other markers (plasmatic or 
urinary) will be assayed in batch and will be reviewed on an ongoing basis through regular safety reviews 
by the DSMB which includes a nephrologist. 
Assays of many other markers are scheduled in order to monitor liver function markers, cardiac safety 
markers, and to follow up the cardiovascular profile which is known to be at risk in NASH patients. 
For cardiac safety, troponin-T and NT-ProBNP will be followed and reviewed on a regular basis by the 
DSMB. In addition, electrocardiogram (ECG) and blood pressure (BP) will be continuously controlled 
throughout the study. 
Liver function will be monitored throughout the study, by assessment of liver enzymes, bilirubin (total or 
conjugated), alkaline phosphatase, and international normalized ratio (INR) reported at each visit. 
In addition, even if no safety concern has been revealed in the previous clinical program, all the biological 
parameters that are known to be affected by PPAR agonists will remain monitored in the Phase III trials, 
such as hematological parameters, adiponectin, or homocysteine. 


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During the Long-term Treatment Period, patients will be monitored by clinical and biological assessment. A 
FibroScan® measurement and noninvasive markers assessment will be performed every 24 weeks, and if 
cirrhosis is suspected, a confirmation by liver biopsy will be performed. 
For additional information see Investigator’s Brochure. 


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2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
2.1.1. 
Surrogate endpoint -Interim analysis 
To evaluate the efficacy of elafibranor QD for 72 weeks versus placebo on resolution of NASH without 
worsening of fibrosis. 
• 
Resolution of NASH is defined as the disappearance of ballooning and disappearance or 
persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not 
qualifying for steatohepatitis. 
• 
Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging 
system and defined as progression of at least one stage. 
2.1.2. 
Long-term endpoint 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis, and the full list of portal hypertension/cirrhosis related events: 
• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
2.2. 
KEY SECONDARY OBJECTIVE – INTERIM ANALYSIS 
To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the 
following endpoint parameter: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring. 


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2.3. 
OTHER SECONDARY OBJECTIVES 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients with improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in steatosis-activity-fibrosis 
(SAF) activity score 
o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (36-Item Short-Form Health Survey [SF-36]) questionnaire). 
• 
To assess Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
 
2.4. 
EXPLORATORY OBJECTIVES 
• 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment for 
PK population analyses. 


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• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
2.5. 
EXPLORATORY OBJECTIVES FOR F1 GROUP 
• 
To explore the following endpoints in elafibranor treated F1 patients in the exploratory group 
relative to placebo at Week 72 and at the end of the Long-term Treatment Period: 
o 
resolution of NASH without worsening of fibrosis. 
o 
percentage of patients with at least 1 point reduction in NASH CRN fibrosis score and 
NAFLD Ishak score. 
o 
percentage of patients with at least 1 point improvement in NAS, steatosis, ballooning, 
lobular inflammation, or portal inflammation. 
o 
percentage of patients with improvement of NAS score of at least 2 points. 
o 
percentage of patients with at least a 1 point improvement in SAF activity score. 
o 
mean changes in NAS score, fibrosis (using NASH CRN or NAFLD Ishak scoring system), 
steatosis, hepatic ballooning, lobular inflammation, portal inflammation, and SAF activity 
score. 
o 
changes in area of fibrosis by morphometry. 
• 
To explore the following endpoints in F1 patients at Week 72 and after the Long-term Treatment 
Period: 
o 
composite endpoint as described in Section 2.1.2. 
o 
cardiovascular events. 
o 
changes in liver enzymes and liver markers. 
o 
changes in noninvasive markers of fibrosis and steatosis. 
o 
changes in lipid parameters. 
o 
variation in body weight. 
o 
changes in insulin resistance and glucose homeostasis markers. 
o 
changes in inflammatory markers. 
o 
changes in cardiovascular risk profile as assessed by Framingham scores. 
o 
changes in quality of life (SF-36 questionnaire). 
• 
To determine PK parameters of elafibranor (GFT505) and GFT1007 after 72 weeks of treatment. 
• 
To assess the tolerability and safety. 
2.6. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor 120 mg 
description of: 
• 
SAE, AE, physical examination, vital signs, medical history, ECG 
• 
hematological parameters 
• 
liver function parameters 
• 
renal function parameters (including urinalysis) 


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• 
cardiac function parameters 
• 
metabolic parameters 
• 
other biochemical safety markers. 
 
 


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3. 
TRIAL DESIGN 
This is a Phase III, randomized, double-blind, parallel groups, placebo-controlled study, evaluating the 
efficacy and safety of elafibranor 120 mg QD versus placebo in an adult NASH population with fibrosis. The 
first double-blind 72-week treatment period will assess the efficacy and safety of elafibranor on the 
resolution of NASH without worsening of fibrosis at the intermediate efficacy analysis, followed by a 
Long-term Treatment Period to assess the prevention of mortality all cause, progression to cirrhosis, and to 
the full list of portal hypertension/cirrhosis related events (see Section 2.1.2). The study will terminate 
upon the 456th patient (excluding exploratory F1 group [see below]) experiencing an event listed in the 
composite endpoint for long-term efficacy evaluation. 
It is planned to randomize patients to either active or placebo treatment in a 2:1 ratio, stratified by type 2 
diabetes, gender (with a capping of women to 40%), and fibrosis stage. Additional patients with fibrosis 
stage 1 (10% of sample size calculated for the F2 and F3 patients) and high risk for progression of NASH 
will also be enrolled for exploratory purposes. 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 2022 F2/F3 patients to either active (1348 patients) or placebo (674 patients) 
treatment in a 2:1 ratio up to 202 additional patients (a maximum level of 10% of the F2/F3 enrolled 
patients) with fibrosis stage of 1 and high risk for progression of NASH (NAS ≥5, F1 patients with 2 of the 
following conditions: persistent elevated ALT, obesity defined by a body mass index (BMI) ≥30, metabolic 
syndrome [National Cholesterol Education Program’s Adult Treatment Panel III {NCEP ATP III definition}], 
type 2 diabetes, or HOMA-IR >6) will also be enrolled, and followed as an exploratory group. The F1 
patients will not be included in the primary interim and final analysis or in the sample size calculation 
(detailed in Section 9.7). As such a total of 2224 patients will be enrolled, including the exploratory F1 
group. 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
Patients who satisfy all eligibility criteria will be randomly allocated to one of the following groups in a 2:1 
ratio: 
• 
Elafibranor 120 mg 
• 
Placebo. 
Randomization to treatment will be stratified to ensure balance of treatment allocation by the following 
3 factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 


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Treatment assignments will be made using an interactive voice/web response system (IXRS). 
3.3. 
DOSE ADJUSTMENT CRITERIA 
Not applicable. Patients will be randomized to a fixed dose with no allowance for dose adjustment. 
3.4. 
DURATION OF STUDY PARTICIPATION 
The estimated duration of the study will be approximately 72 months, based on 456 patients experiencing 
an event described in Section 2.1.2 at an assumed annual rate event of 7%. However, this may be 
redefined according to the actual occurrence of events (described in Section 2.1.2) during the confirmatory 
part of the study (Long-term Treatment Period). 
3.5. 
STUDY PERIODS 
The study will comprise 3 periods. The Screening Period (-12 to -1 weeks) will precede a 72-week 
double-blind First Treatment Period and a Long-term Treatment Period up to the occurrence of a 
prespecified number of events. 
Study procedures are summarized in Table 1, Table 2, Figure 1, and Figure 2. 
Schedule: 
• 
Week -12 to Week -1 prior to Randomization: Screening Period (screening visits SV1 to SPV). 
• 
Week 0 to Week 72: First Treatment Period with Elafibranor or placebo for 72 weeks (visits V1 to 
V7). 
• 
Week 72 to end of study (EOS): Long-term Treatment Period with elafibranor or placebo until 456 
patients experience an event listed in Section 2.1.2 (visits V8 to Vn). 
3.6. 
SCREENING PERIOD 
3.6.1. 
Screening visits SV1 (Week -12 to Week -8) and SV2 (Week -12 to 
Week -4): 
The following screening procedures will be performed for all potential patients at SV1 conducted between 
Week -12 and Week -8 prior to Randomization: 
• 
Signature of informed consent witnessed by the Investigator or designated person. 
• 
Patient number allocation via IXRS. 
• 
Check medical history/demographics. 
• 
Check inclusion/exclusion criteria (described in Section 4). 
• 
Physical examination (described in Section 6.2.1). 


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• 
Adequate diet recommendations (described in Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), and tobacco habits. 
• 
Record vital signs (described in Section 6.2.2). 
• 
Record height, weight, and waist circumference. 
• 
Check concomitant/prior medication (within 30 days prior to Screening) (described in Section 7.10 
and APPENDIX III: Permitted/Non-permitted medication) 
• 
Check if a liver biopsy with confirmed NASH and fibrosis is available, and, if so send sample for 
central confirmation of NASH diagnosis (described in Section 6.1.1.2). This historical diagnostic 
biopsy should be obtained within 6 months prior to the planned Randomization Visit V1. 
• 
Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 and 
Section 8). 
The Screening biological assessment (SB1 will be scheduled at SV1). 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked at least Week -4 (period between Screening and Week -4) prior to the planned Randomization V1. 
The following biological assessments (detailed in Table 2) will be performed at SB1: 
• 
Blood samples (described in Table 2). 
• 
Whole blood, plasma & serum bank samples (only if additional genetic and biomarker ICF signed). 
• 
Urinalysis dipstick. 
• 
Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
For DILI adjudication, in order to define an adequate baseline value for the liver parameters (AST, ALT, 
total bilirubin, INR), at least 2 consecutive assessments in at least 8 weeks apart between visit SV1 and V1 
should be performed. Visits SV1 and V1 should be scheduled according to this requirement. 
If needed, a retesting of abnormal HbA1c, estimated glomerular filtration rate (eGFR) or creatine 
phosphokinase (CPK) results or additional testing of hepatitis C virus (HCV) RNA, may be performed during 
the screening window to determine the eligibility for the study as described in exclusion criteria 5, 13, 31, 
and 32 (see Section 4.2 and Section 3.11). 
At visit SV1, preliminary entrance criteria will be reviewed. Potentially eligible patients will be asked if they 
agree to participate in the study and sign the ICF. Each patient who will have signed the ICF will be 
allocated a patient number composed of 7 digits which is generated by the IXRS. 
 First 3 digits corresponding to the ISO numeric country code (this number will be predefined), 
 Next 2 digits corresponding to the site number (this number will be predefined), 
 Last 2 digits corresponding to the numerical order of the patient entry at the study site. 


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A specific IXRS procedure manual will be provided to the Investigator. 
3.6.2. 
Screening Visit SV2 (liver biopsy if required, Week -12 to Week -4): 
If no diagnostic liver biopsy (within 6 months of V1) is available at visit SV1, an additional SV2 visit will be 
booked by at least Week -4 for a liver biopsy to be performed (described in Section 6.1.1.1). Blood 
samples for coagulation (detailed in Table 2) will be taken and tested at a local laboratory prior to the liver 
biopsy. Liver biopsy samples will be sent for central confirmation of NASH diagnosis (described in Section 
6.1.1.2). 
During this visit AEs (from the time of signing the ICF) will also be checked (described in Section 6 and 
Section 8). 
3.6.3. 
Screening Phone Visit SPV (Week -1): 
Upon receipt of the NASH diagnosis confirmation and the SB1 or any retesting/additional testing results 
from the central laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, and biological 
ones), the Investigator will inform the patient of his/her inclusion/noninclusion status by a phone call 
within 1 week prior to the Randomization Visit V1. In case of ineligibility, the patient should be contacted 
as soon as possible. 
3.7. 
FIRST TREATMENT PERIOD (WEEK 0 TO WEEK 72) 
Efficacy of elafibranor versus placebo on resolution of NASH without worsening of fibrosis will be evaluated 
in this first period treatment of 72 weeks. 
The NASH will be evaluated for inclusion by a centrally-read liver biopsy taken within 6 months prior to 
Randomization (if no historical biopsy is available for NASH diagnosis, a liver biopsy will be performed 
during the Screening Period) with: 
• 
Presence of NASH, with at least a score of 1 in each component of the NAS score (steatosis 
scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) AND 
NAS score ≥4. 
• 
Fibrosis stage 2 and 3. 
A group of patients (n=202, 10% of each group) with F1 fibrosis, NAS ≥5, and concomitant 
cardiometabolic comorbidities, which are associated with rapid progression of the disease (listed in 
Section 3.1), will also be enrolled and followed as an exploratory group. 
During these first 72 weeks of treatment, visits will be scheduled every 12 weeks. Clinical and biological 
evaluation will be performed during this First Treatment Period. 


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At the end of the 72-week treatment period, a biopsy will be performed for all the patients under 
treatment in order to evaluate the effect of elafibranor on the liver histology. 
When 1023 patients (F2-F3) complete Week 72 (or discontinue early from the study), an interim analysis 
will be performed and potentially filed for initial market approval under Subpart H or conditional approval, 
(see Section 9.8.1 for details). 
During the First Treatment Period the patients will return to the site for visits every 12 weeks (±1 week) 
from the Randomization Visit (V1); however the maximum time period between visits is to be 96 days due 
to the study drug supply provided to the patient. 
A diagnosis of any event listed in the primary composite endpoint described in Section 1.9.2 will result in 
the permanent discontinuation of study drug and discontinuation from the study, following an end of study 
treatment (EOT) Visit as described in Section 3.9 and Section 5.2.2). 
3.7.1. 
Randomization Visit V1 (Week 0): 
Eligible patients will return to the site at the Randomization Visit V1 and then every 12 weeks in the First 
Treatment Period of the study until the first 72 weeks of treatment (V7) (interim analysis). The patient will 
be contacted at least 1 week before each visit to be reminded of procedures and investigational product 
(IP) return. 
If the patient is eligible, the Investigator will register the patient for randomization in the IXRS, prior to any 
other study procedures. If the system confirms the randomization, it will provide the Investigator with a 
treatment number for the patient. 
The following will be performed only at V1: 
• 
Check inclusion/exclusion criteria (detailed in Section 4). 
• 
Randomization to one of 2 treatments groups (elafibranor or placebo in 2:1 ratio, detailed in 
Section 3.2) via the IXRS. 
3.7.2. 
First Treatment Period visits V1 to V7 (Week 0 to Week 72): 
The following procedures will be performed at each of the 12-week visits from V1 to V7: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 


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• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
Quality of life assessment (V1, V3, V5, and V7, only; described in Section 6.2.5) 
• 
Check AEs (all visits) and occurrence of any clinical outcome (from V2 onwards) (described in 
Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record result of home pregnancy tests (to be performed ever 4 week [see Figure 2]) since 
previous visit (for WOCBP only, every visit from V2) 
• 
Record waist circumference (V1, V3, V5, and V7, only) 
• 
12-lead ECG (V1, V4, and V7, only; described in Section 6.2.3) 
• 
FibroScan (V1 and V7 only, described in Section 6.2.4) 
• 
Drug accountability (every visit from V2). 
Additional procedures to be performed at V7 are: 
• 
PK blood sampling (2 hours and 5 hours 45 minutes postdose, see Section 6.1.4). 
• 
Liver biopsy (described in Section 6.1.1). Note: the liver biopsy may be performed at V7 or during 
a separate visit that occurs within the V7 window of 72 weeks ± 1 week from V1. Liver biopsy 
samples will be sent for central histological evaluation. 
• 
Blood samples for coagulation taken (platelets count and prothrombin time [PT] [INR]; described 
in Table 2) and tested at a local laboratory prior to the liver biopsy. 
3.8. 
LONG-TERM TREATMENT PERIOD 
The main objective to be evaluated during the Long-term Treatment Period will be the prevention of 
progression to cirrhosis, or to portal hypertension/cirrhosis related events (as described in Section 1.9.2. 
After the 72-week biopsy, patients will continue in the double-blind Long-term Treatment Period, receiving 
the same treatment as assigned at V1 (elafibranor 120 mg or placebo). Patients will be monitored by 
notably measuring the appearance of cirrhosis (based on FibroScan measurement associated with 
biological and/or clinical assessments and confirmed by biopsy). 
At or after the 72-week biopsy, a diagnosis of any event listed in the primary composite endpoint described 
in Section 1.9.2 will result in the permanent discontinuation of study drug and discontinuation of the study 
following the EOT Visit (as described in Section 3.9 and Section 5.2.3). 


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3.8.1. 
Long-term Treatment Period visits (V8 to Vn) 
Patients will return to the site every 24 weeks during the Long-term Treatment Period. The patient will be 
contacted at least 1 week before each visit to be reminded of procedures and IP return. 
The following procedures will be performed at each visit from V8 to Vn: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Confirmation of adequate diet and lifestyle compliance (described in Section 5.1.1 and APPENDIX 
II: Adequate diet and lifestyle recommendations), alcohol restrictions (described in Section 5.1.2), 
and tobacco habits 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
Quality of life assessment (V8, V9, V11, and 48 weekly thereafter Section 6.2.5) 
• 
Check AEs and occurrence of any clinical outcome (described in Section 6 and Section 8) 
• 
Study placebo or drug dispensation (described in Section 7.4, with the exception of the final Vn 
visit) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Provision of home pregnancy test kits (for WOCBP only) 
• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (every 48 weeks from V9; described in Section 6.2.3) 
• 
FibroScan (described in Section 6.2.4) 
• 
Drug accountability 
• 
Liver biopsy (at approximately 4 years [V13], and in case of suspected liver cirrhosis, described in 
Section 6.1.1). Liver biopsy samples will be sent for central histological evaluation 
• 
Blood samples for coagulation taken (platelets count and PT [INR]; described in Table 2) and 
tested at a local laboratory prior to the liver biopsy. 
3.8.2. 
Long-term Treatment Period phone visits (PV1 to PVn) 
Phone visits will be scheduled every 24 weeks starting 12 weeks after Visit 7 for data collection on clinical 
outcomes, safety, home pregnancy test results, and IP compliance control. If any information during this 


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phone contact requires a visit, the Investigator may decide to perform an unscheduled visit (described in 
Section 3.11.2). IXRS registration will be performed for each phone visit. 
3.9. 
END OF STUDY TREATMENT VISIT 
At the EOS (upon occurrence of the expected number of events), all patients will be asked to stop 
treatment and undergo an EOT Visit 30 days after the final administration of study drug. 
All patients who permanently discontinue their study medication will undergo an EOT Visit 30 days after 
the final administration of study drug. Patients who permanently discontinue study drug for any reason 
other than an event listed in the primary composite endpoint for long-term efficacy described in Section 
1.9.2 will remain, upon agreement, in the study after the EOT Visit and be followed up to evaluate efficacy 
outcomes and safety through 24 weekly phone call visits as described in Section 3.10 and Section 5.2. 
If a patient discontinues from the study, every attempt should be made to have the patient return to the 
site and complete the EOT Visit 30 days after the final administration of study drug. For details of the EOT 
Visit see Table 1, Table 2, Figure 1, and Figure 2. 
The following procedures will be performed at the EOT Visit: 
• 
IXRS registration 
• 
Physical examination (described in Section 6.2.1) 
• 
Record vital signs and weight (described in Section 6.2.1 and Section 6.2.2) 
• 
Check 
concomitant/prior 
medication 
(described 
in 
Section 
7.10 
and 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
Quality of life assessment (described in Section 6.2.5) 
• 
Check AEs and occurrence of any clinical outcome(described in Section 6 and Section 8) 
• 
Blood samples (described in Table 2) 
• 
Plasma & serum bank samples (only if additional genetic and biomarker ICF informed consent 
signed) 
• 
Urinalysis and urinary dipstick (described in Table 2) 
• 
Urinary pregnancy test (for WOCBP only) 
• 
Record results of home pregnancy tests (to be performed every 4 weeks [see Figure 2]) since 
previous visit (for WOCBP only) 
• 
Record waist circumference 
• 
12-lead ECG (described in Section 6.2.3) 
• 
Drug accountability. 
Patients discontinuing study drug or discontinuing the study will be asked to return all used and unused 
study treatments at the EOT Visit. 


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3.10. FOLLOW-UP FOR PATIENTS WHO HAVE PERMANENTLY DISCONTINUED STUDY DRUG 
Patients who have permanently discontinued study drug due to an event listed in the primary composite 
endpoint for long-term efficacy described in Section 1.9.2 will be discontinued from the study following the 
EOT Visit and have no further follow-up. 
Patients who have permanently discontinued study drug for any other reason will remain, upon agreement, 
in the study and will be followed up with 24 weekly phone visits (±2 weeks from EOT Visit) following the 
EOT Visit to report safety, diagnosis of cirrhosis and occurrence of clinical outcomes (as listed below) 
including liver and cardiovascular events until EOS or the occurrence of an event listed in the primary 
composite endpoint for long-term efficacy (described in Section 1.9.2), whichever is sooner. 
The following procedures will be performed during the follow-up phone visit for patients who have 
permanently discontinued study drug: 
• 
IXRS registration. 
• 
Reporting of safety information regarding: 
o 
any new AEs 
o 
resolution of previous AEs 
o 
change in severity of existing AEs 
o 
occurrence of any cardiovascular events 
o 
occurrence of diabetes (for patients not previously diagnosed with diabetes) 
o 
worsening of diabetes (for patients previously diagnosed with diabetes). 
• 
Reporting of any change in diet and life style factors 
• 
Reporting of any change (quantitative or qualitative) in therapies post study drug discontinuation 
• 
Reporting of cirrhosis diagnosis (patient to be asked if they have had any histological confirmation 
of cirrhosis) 
• 
Reporting of any of the following events (primary composite endpoint for long-term efficacy 
evaluation): 
o 
liver transplantation 
o 
MELD score ≥15 
o 
HCC 
o 
hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence 
of: 
 
variceal bleed 
 
hepatic encephalopathy 
 
spontaneous bacterial peritonitis 
 
uncontrolled ascites 
 
hepatorenal syndrome 
 
hepatopulmonary syndrome 


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 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy 
(provided that these lead to hospitalization or transfusion). 
o 
death due to any cause. 
3.11. OPTIONAL VISITS 
3.11.1. 
Retesting screening visits 
Upon receipt of results from biological assessment done at SV1, and in case a retesting or additional 
testing is needed according to the selection criteria, an additional visit will be scheduled according to the 
recommended timeframe for retesting. 
Permitted retesting or additional testing in case of abnormal value at SV1 are: 
• 
CPK: can be repeated prior to Randomization (V1) within 1 to 2 weeks after initial test. 
• 
eGFR measurement: can be repeated prior to Randomization (V1) within the following timeframe: 
minimum 4 weeks after initial test and maximum 2 weeks prior to planned Randomization. 
• 
HCV RNA testing, in case positive HVC Ab test: required latest 2 weeks prior to Randomization 
(V1). 
• 
HbA1c: can be repeated at the latest 2 weeks prior to Randomization (V1). 
3.11.2. 
Unscheduled visits 
An unscheduled visit is defined as any visit to the study unit outside of the protocol-evaluation timepoints 
where the patient is seen by study unit personnel, e.g., when follow-up assessments are required for 
safety reasons or when repeat measurements are required out of the Screening Period (either to confirm a 
measurement or in case of errors, measuring device failure, etc). 
Unscheduled visits will be needed for patients who may require further follow-up due to safety. 
3.12. EXPLORATORY/ANCILLARY SUBSTUDY 
Exploratory substudies might be performed during the study in sites that have the corresponding 
capability. Specific study documents will be prepared and Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and authority approvals shall be obtained when applicable. 
 


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4. 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. 
Males or females aged from 18 to 75 years inclusive at first Screening Visit. 
2. 
Must provide signed written informed consent and agree to comply with the study protocol. 
3. 
BMI ≤45 kg/m². 
4. 
Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral 
oophorectomy, medically documented ovarian failure, or >50 years of age with cessation of menses 
for at least 12 months due to ovarian failure) or using efficient double contraception: hormonal 
contraception (including patch, contraceptive ring, etc), intra-uterine device, or other mechanical 
contraception method + condom or diaphragm or spermicide for the full duration of the study and for 
1 month after the end of treatment. 
5. 
Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides 
(biopsy obtained within 6 months prior to Randomization or during the Screening Period) with at least 
1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and 
lobular inflammation scored 0-3). 
6. 
NAS score ≥4. 
7. 
Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. 
For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning 
with a NAS score >5 and 2 of the following conditions: persistent elevated ALT, obesity defined by a 
BMI ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR ≥6. 
8. 
Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no 
historical biopsy within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of 
treatment for assessment of the treatment effects on NASH, as well as another in case of suspicion of 
cirrhosis, (to have a histological confirmation), and a final liver biopsy after approximately 4 years of 
treatment (V13), unless a biopsy has already been performed within the year. 
9. 
Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (PUFAs, >2 g/day), or 
ursodeoxycholic acid from at least 6 months prior to diagnostic liver biopsy. 
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by 
anti-diabetic drugs, no change is allowed within 6 months prior to diagnostic liver biopsy, under the 
following conditions: 
• 
no change in dose for patients treated by GLP-1 agonists 


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• 
no qualitative change (i.e., implementation of a new anti-diabetic therapy) for patients treated by 
metformin, dipeptidyl-peptidase 4 inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, 
sulfonylurea medications, or insulin. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. 
Known heart failure (Grade I to IV of New York Heart Association classification). 
2. 
History of efficient bariatric surgery within 5 years prior to Screening. 
3. 
Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 
4. 
Type 1 diabetes patients. 
5. 
Patients with decompensated diabetes (HbA1c >9.0%). If abnormal at the first Screening Visit, the 
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated 
abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 
6. 
Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at 
least 6 months before the diagnostic liver biopsy. 
7. 
Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening 
such as: acute cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease 
(angina pectoris, myocardial infarction, revascularization procedures). 
8. 
Weight loss of more than 5% within 6 months prior to Randomization. 
9. 
Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, 
NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are 
excluded. 
10. Current or recent history (<5 years) of significant alcohol consumption. For men, significant 
consumption is typically defined as higher than 30 g pure alcohol per day. For women, it is typically 
defined as higher than 20 g pure alcohol per day. See APPENDIX IV: Alcohol comparison table. 
11. Patients who have donated blood or blood products within 1 month prior to Screening or who plan to 
donate blood or blood products at any time during the trial and in the 2 months following the end of 
the study. 
12. Pregnant or lactating females or females planning to become pregnant during the study period. 
13. Other well documented causes of chronic liver disease according to standard diagnostic procedures 
including, but not restricted to: 
• 
Positive hepatitis B surface antigen (HBsAg) 
• 
HCV RNA 
• 
Suspicion of drug-induced liver disease 
• 
Alcoholic liver disease 
• 
Autoimmune hepatitis 


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• 
Wilson’s disease hemochromatosis 
• 
Primary biliary cirrhosis, primary sclerosing cholangitis 
• 
Genetic hemochromatosis 
• 
Known or suspected HCC 
• 
History or planned liver transplant, or current MELD score >12. 
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the 
recommendations of National Law in force. 
15. Patients who cannot be contacted in case of emergency. 
16. Known hypersensitivity to the investigation product or any of its formulation excipients. 
17. Patients with previous exposure to elafibranor. 
18. Patients who are currently participating in, plan to participate in, or have participated in an 
investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior 
to Screening. 
Concomitant medications (see APPENDIX III: Permitted/Non-permitted medication): 
19. Fibrates are not permitted from 2 months before Randomization. Patients that used statins or 
ezetimibe before Screening may participate if the dosage has been kept constant for at least 2 months 
prior to Screening. 
20. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: 
corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen 
(Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to 
Screening. 
21. Currently taking any medication that could interfere with study medication absorption, distribution, 
metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., 
indomethacin, which are not permitted from Randomization. 
Associated illnesses or conditions: 
22. Any medical conditions that may diminish life expectancy to less than 2 years including known 
cancers. 
23. Evidence of any other unstable or, untreated clinically significant immunological, endocrine, 
hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 
24. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain. 
In addition to the above criteria, patient should not present any of the following biological exclusion 
criteria: 
25. Positive anti-human immunodeficiency virus (HIV) antibody. 


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26. AST and/or ALT >10 x the upper limit normal (ULN). 
27. Total bilirubin >25 µmol/L (1.5 mg/dL). 
28. INR >1.4. 
29. Platelet count <100,000/mm3. 
30. Serum creatinine levels >135 μmol/L (>1.53 mg/dL ) in males and >110 μmol/L (1.24 mg/dL) in 
females. 
31. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients 
with markers of kidney damage or eGFR of less than 60 ml/min/1.73 m2). If abnormal at the first 
Screening Visit, the eGFR measurement can be repeated prior to the Randomization within the 
following timeframe: minimum 4 weeks after initial test and maximum 2 weeks prior to planned 
Randomization. A repeated abnormal eGFR (less than 60 ml/min/1.73 m2) leads to exclusion. 
32. Unexplained serum CPK >3 x the ULN. In case of explained elevated CPK >3 x the ULN, the 
measurement can be repeated prior to Randomization. In this case, retest should be performed within 
1 to 2 weeks after initial test. A CPK retest >3 x ULN leads to exclusion. 
 
 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (see Table 1, Table 2, 
Figure 1, and Figure 2) and in Section 3. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of day for 
each patient. A patient may be seen at any time for reasons of safety. 
During each visit, lifestyle and study recommendations will be repeated, vital signs will be measured, and 
the patient will be queried in the form of an open question regarding new or continuing events. 
Procedures for premature discontinuation after SV1 are described in Section 5.2. 
5.1. 
LIFESTYLE RECOMMENDATIONS AND STUDY RECOMMENDATIONS 
5.1.1. 
Standard diet and exercise recommendations 
Standard diet and exercise recommendations given by the Investigator during SV1 will have to be 
maintained throughout the study. These recommendations will be based on Therapeutic Lifestyle Change 
(TLC) counseling (or local equivalent) according to NCEP ATP III guidelines. The essential components of 
TLC and the macronutrient recommendations for the TLC diet are detailed in APPENDIX II: Adequate diet 
and lifestyle recommendations. 
Assessment of dietary and lifestyle compliance will occur at each visit by asking the patient 2 questions to 
confirm if they have remained compliant to the diet and lifestyle recommendations (“Have you remained 
compliant to the recommended diet since the last visit?” and “Have you remained compliant to the 
recommended physical activity since the last visit?”. A yes/no response will be recorded in the electronic 
care report form (eCRF). 
5.1.2. 
Dietary and fluid restrictions 
The following restrictions should be applied to patients in this trial from SV1 through to the end of the 
study: 
• 
Patients will be required to fast (no food or drink other than water) for at least 12 hours prior to all 
blood sampling. As such, patients should not consume any breakfast or take any medication 
(including study medication) in the morning prior the blood sampling. In case the patients do not 
fast before a visit, a new appointment will be scheduled within 2 days. 
• 
On each study visit day, study treatment will be taken in fasted conditions after the blood sampling 
(which corresponds to the day of the visit). 
• 
During the 48 hours preceding each study visit, patients should not perform strenuous exercise. 


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• 
Patients are to avoid consumption of dietary supplements such as anti-oxidant (including, but not 
limited to Vitamin A, Vitamin C, provitamin A, selenium, and polyphenol). 
• 
Alcohol consumption should be limited during the study duration and registered in the eCRF. 
Alcohol consumption of more than 20 g per day for women and 30 g per day for men is considered 
abusive (see APPENDIX IV: Alcohol comparison table). A standard drink is equal to 14.0 grams 
(0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in: 
o 
12-ounces/350 ml of beer (5% alcohol content) 
o 
5-ounces/150 ml of wine (12% alcohol content) 
o 
1.5-ounces/50 ml (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, 
whiskey). 
Concomitant therapy is restricted and any change to treatment or introduction of a new treatment should 
be discussed with the Investigator before doing so (see Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication). 
5.1.3. 
Ultra-violet light exposure 
As a conservative approach patients will be advised to avoid extended ultra-violet light exposure without 
protection from SV1 through to the end of the study (see Section 1.4.4.4). 
5.1.4. 
Home pregnancy test for women of childbearing potential 
Women of childbearing potential are required to perform a pregnancy test every 4 weeks. Home pregnancy 
test kits will be supplied at each visit to WOCBP and these are to be performed as per the kit instructions 
every 4 weeks between study visits. Negative results are to be reported at the next scheduled visit or 
telephone visit (see Table 1 and Figure 2). In the event of a positive result the patient must discontinue 
study drug immediately and report the result to the Investigator as soon as possible (see Section 8.6.1) 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Handling of patient withdrawal 
Patients will be informed that they have the right to discontinue the study at any time, for any reason, 
without affecting future management and treatment. 
5.2.2. 
Permanent discontinuations of study drug 
In some instances, it may be necessary for a patient to permanently discontinue study drug. The patient 
may be discontinued from study drug at any time at the discretion of the Investigator or Sponsor for 
safety, behavioral, or administrative reasons. In keeping with the ITT analysis, the patient will not be 
permanently discontinued from the study. 


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The reason for permanent discontinuation of study drug should be documented in the eCRF and the 
Medical Monitor informed. If the discontinuation of study drug is due to an AE, the event should be 
documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
Occurrence of any event listed in the composite endpoints for long-term efficacy evaluation (see 
Section 1.9.2) 
• 
In the opinion of the Investigator, any AE, SAE (described in Section 8), or significant change in a 
laboratory value that warrants permanent discontinuation of study drug therapy. Investigators are 
advised to call the Medical Monitor prior to making such a decision 
• 
Occurrence of repeated hypoglycemic episodes without possibility for a down titration of 
background therapy that may put the patient at risk with continued participation 
• 
Non-permitted concomitant medication (described in Section 7.10 and APPENDIX III: 
Permitted/Non-permitted medication) 
• 
Female patients who are pregnant (see Section 8.6.1) or are breastfeeding or who do not agree to 
use a reliable method of birth control during the study will be permanently discontinued from study 
drug 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 
Patients permanently discontinued from study drug will be requested to stop taking study drug and attend 
an EOT Visit 30 days after the last administration of study drug (described in Section 3.9). 
If the study drug is discontinued due to the occurrence of any event listed in the composite endpoints for 
long-term efficacy evaluation (see Section 1.9.2), the patient will also be discontinued from the study with 
no further follow-up after the EOT Visit. 
If the study drug is discontinued due to any reason other than the occurrence of any event listed in the 
composite endpoints for long-term efficacy evaluation, the patient will undergo, if agreed, 24 weekly 
telephone visits (described in Section 3.10) after the EOT Visit until the EOS or the occurrence of any event 
listed in the primary composite endpoints for long-term efficacy evaluation (see Section 1.9.2), whichever 
is sooner. 
5.2.3. 
Patient discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be low, occurring if the 
patient withdraws consent, or if enrollment in any other clinical trial involving an investigational product, or 
enrollment in any other type of medical research judged not to be scientifically or medically compatible 
with this study, occurs. 


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At the time of discontinuing from the study, the Medical Monitor and IXRS should be contacted, and, if 
possible, an EOT Visit should be conducted (see Section 3.9). The patient will be permanently discontinued 
from the study at that time with no further follow-up and the date the patient is withdrawn from the study 
and the reason for withdrawal should be appropriately documented in the eCRF. During the study close-out 
period, survival status will be collected within legal and ethical boundaries for all patients randomized who 
withdrew participation from the study. 
Where possible, patients withdrawn from the study will be followed until resolution of all their SAEs or until 
the unresolved SAEs are judged by the Investigator to have stabilized. 
 
5.2.4. 
Patients lost to follow-Up 
A patient would be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. Site personnel are expected to make diligent attempts to 
contact patients who fail to return for a scheduled visit or were otherwise unable to be followed up by the 
site. Vital status will be collected within legal and ethical boundaries for all patients randomized, including 
those who did not get study drug. Vital status will be searched in public sources during the study close-out 
period. If vital status is determined, the patient will not be considered lost to follow-up. 
5.2.5. 
Replacement 
No patient replacements are permitted in this study. 
5.2.6. 
Premature discontinuation of the study 
Premature termination of this clinical trial may occur because of a Regulatory Authority decision, change in 
opinion of the IRB/IEC, drug safety problems, DSMB recommendations, or at the discretion of the Sponsor. 
In addition, the Sponsor retains the right to discontinue development of the study treatment at any time. 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After such a 
decision, the Investigator must contact all participating patients within a reasonable period of time. As 
directed by the Sponsor, all trial materials must be collected and all eCRFs completed to the greatest 
extent possible. 
Furthermore, the Investigator can decide to prematurely discontinue the study. In that event, the 
Investigator must notify the Sponsor immediately of his/her decision and give the reason in writing. 
Prompt compliance with this requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
In all cases, ethics committee (IRB/IEC) and Health Authorities should be informed. 


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If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related study 
materials must be returned to the Sponsor. 
 
 


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6. ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
6.1.1. 
Histological assessments 
A liver biopsy (see Section 6.1.1.1 for recommendations) will be performed at baseline, after 72 weeks of 
treatment, in case cirrhosis is suspected at any interim visit during the Long-term Treatment Period (based 
on FibroScan and biological assessments) and after approximately 4 years of treatment (V13) unless a 
biopsy has been performed within the previous year. 
A Laboratory Manual will be provided to each trial site. The manual will outline the collection process, and 
shipping requirements for the specific central laboratory. 
6.1.1.1. 
Recommendations related to liver biopsy 
Before performing a percutaneous liver biopsy, there must be a clearly defined indication for the biopsy, 
and the risks to the patient should not outweigh the potential benefits. 
Patients who are about to undergo a percutaneous liver biopsy should have had some form of imaging of 
the liver within the preceding weeks. This will allow the detection of abnormal anatomy in the area of the 
proposed biopsy. 
The patient’s platelet count and PT should be checked according to local hospital standards before the date 
of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they are in 
everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no more than 
4 seconds over the control, and a normal bleeding time are acceptable for performing percutaneous liver 
biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. If these conditions are 
not all respected, a safer option would be to perform the liver biopsy by transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution in 
liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gage needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 hours 
after the procedure. 


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The biopsies will be sent to the central laboratory and then to a central reader who will read the biopsies 
to determine the eligibility to the study according the fibrosis stage and consistency with NASH diagnosis. 
Biopsy slides will be blinded for patient and visit identification prior to central reading. 
6.1.1.2. 
Liver biopsy reading for NAS and NASH CRN fibrosis score 
Histological changes from baseline to Week 72 and any follow-up biopsy will be evaluated. Liver biopsy 
samples will be sent to the central pathology laboratory (Hôpital Beaujon, 100 Boulevard du Général 
Leclerc, 92110 Clichy – France) where they will be read and scored. Scores for total NAS, steatosis, 
ballooning, lobular inflammation, or portal inflammation, as well as fibrosis scores (both by NASH CRN 
scoring system, and NAFLD Ishak scoring system) and fibrosis area by morphometry will be evaluated. 
6.1.2. 
Biological assessments 
All blood samples for efficacy and/or for safety assessment (as described in Table 2) will be returned and 
centralized by the central laboratory (BARC: Ghent – Belgium, New York – USA, Sydney – Australia, or 
Johannesburg – South Africa) and specific analyses will be performed by another laboratory (GENFIT- 
Loos, France). 
A laboratory manual will be provided to each trial site. 
The manual will outline the collection process and shipping requirements for the specific central laboratory. 
Blood sampling will be performed by trained personnel at each site. Blood samples will be processed and 
shipped as outlined in the laboratory manual. Refer to the laboratory manual for exact amounts of blood 
required for each test. 
For all visits, laboratory results will be available at sites approximately 24 hours after receipt of samples. 
Final results will be couriered to sites. Laboratory reports should be reviewed, signed, and dated by the 
Investigator as soon as they are received. The Investigator should comment upon out of range parameters 
and assess clinical significance. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting (to 
be performed at Retesting Screening visits) is limited to HbA1c, eGFR, CPK, and HCV RNA as described 
Section 3.11. 
6.1.2.1. 
Laboratory assessments 
Clinical laboratory evaluations (including hematology, blood chemistry, and urinalysis) will be measured at 
every visit as described in Table 2. 
Hematology and urinalysis (dipstick) will be measured at all visits. Both blood and urine sample will be 
transported to the central laboratory for testing and analysis. 
At Screening, the Screening Visit 1 chemistry panel will be measured. 


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The V1 to Vn total chemistry panel and urine analysis will be measured at all visits from V1 to EOT visits. 
6.1.2.2. 
Urinary pregnancy tests 
Urinary pregnancy tests will be supplied to each site to perform a pregnancy diagnostic at each visit during 
the study on WOCBP. 
6.1.2.3. 
Serology (SB1) 
Screens for a hepatitis panel and HIV antibodies will be performed at SV1: 
• 
HIV ab I/II 
• 
HBsAg 
• 
HCV ab (positive HCV RNA in case HCV ab>0, to be performed at Retesting Screening Visit) 
6.1.2.4. 
Other parameters 
Liver markers, calculated fibrosis and steatosis index, safety, and inflammatory markers, as well as special 
glycemic and lipid parameters, will be measured at V1, V3, V5, and V7 during the First Treatment Period, 
at each visit during Long-term Treatment Period, and at the EOT visit. CHI3L1 will only be tested at V1, 
V7, and V13 (at the time of the approximate 4 year biopsy). 
6.1.3. 
Constitution of biobank 
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of NASH or other related diseases, 
an additional amount of serum & plasma will be kept at each visit (including Screening visits) from patients 
who have given their consent for these additional analyses by signature of the genetic and biomarker ICF. 
These samples will be used: 
• 
To discover or validate biomarkers in NASH and related diseases. 
• 
To investigate the role of selected single nucleotide polymorphisms in the response to 
treatment. 
These samples will be destroyed 3 years after study results at the latest. 
6.1.4. 
Pharmacokinetics evaluation 
6.1.4.1. 
Description of pharmacokinetic evaluation parameters 
The aim of the PK part is to perform end of the First Treatment Period PK population analyses and to 
assess PK among subgroups of patients. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 2 timepoints 
(2 hours and 5 hours 45 minutes post dosing) after 72 weeks repeated once a day administrations (V7). 


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Pharmacokinetic parameters will be determined from elafibranor and GFT1007 plasma concentrations using 
a model established from a compartmental analysis. 
6.1.4.2. 
Pharmacokinetic analysis 
The PK part will be conducted at ADME BIOANALYSES (75, Chemin de Sommières - 30310 
Vergèze - France) in compliance with the Standard Operating Procedures in use at ADME BIOANALYSES. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated by ADME BIOANALYSES (References: PKH/MOA/528). 
6.1.4.3. 
Pharmacokinetic blood sampling timepoints 
Blood sampling will be performed for elafibranor and main active metabolite GFT1007 plasma 
concentration measurements, at the 2 timepoints (2 hours and 5 hours 45 minutes post dosing) after 
72 weeks of treatment. 
6.1.4.4. 
Pharmacokinetic blood handling procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® opaque tubes (Becton Dickinson 
UK Ltd., Oxford) and plasma will be separated in a refrigerated centrifuge (ca. +4°C) at ca. 2500 rpm for 
15 minutes and a volume of exactly 1 mL of plasma will be dispensed in a polypropylene opaque tube for 
the aliquot 1 and 1.5 mL of plasma for the aliquot 2. The plasma samples will be stored at –80°C/-112°F at 
the site facilities. 
Thereafter, the plasma samples will be transported, in dry ice, first to the central laboratory (as for all the 
other blood samples) where they will be stored at –80 ± 10°C (-112 ± 50°F) until shipped to ADME 
BIOANALYSE to be submitted to analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical examination 
A physical examination will be performed and weight measured at each visit (with the exception of the 
potential SV2). Height will be measured at SV1 only. 
Weight is measured in patient in underwear and with an empty bladder. Scale for weight must be the 
same for a given patient throughout the visits. 
6.2.2. 
Vital signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit (with the 
exception of the potential SV2 visit) according to the “Recommendations for Blood Pressure Measurement 
in Humans and Experimental Animals” published in an American Heart Association scientific statement. 


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6.2.2.1. 
Important points for clinical blood pressure measurement: 
• 
The patient should be seated comfortably with the back supported and the upper arm bare without 
constrictive clothing. The legs should not be crossed. 
• 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% 
of the arm circumference. 
• 
When using a mercury sphygmomanometer, the mercury should be deflated at 2 to 3 mm/s, and the 
first and last audible sounds should be taken as systolic and diastolic pressure. The column should be 
read to the nearest 2 mmHg. 
• 
Neither the patient nor the observer should talk during the measurement. 
Systolic BP and diastolic BP will be measured after 5 minutes rest in the seating position with a standard 
mercury sphygmomanometer or a validated sphygmomanometer. Validated manometer has to be the 
same for a given patient throughout the visits. 
6.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, V4, and V7 in the First Treatment Period, every 48 weeks in 
the Long-term Treatment Period starting at V9, and at the EOT Visit. 
Electrocardiograms will be recorded using 12-lead ECG recorders following after 10 minutes rest in the 
supine position. A minimum of 3 cycles will be recorded per lead. 
The ECGs will be analyzed by the Investigator. Any potential clinical significance of ECG changes will be 
determined by the Investigator with relation to the patient’s medical history, physical examination, and 
concomitant medications and recorded in the eCRF. 
6.2.4. 
FibroScan 
A FibroScan exam will be performed at V1 and V7 in the First Treatment Period, and at each visit in the 
Long-term Treatment Period. 
For models not allowing the capture of results, a FibroScan measurement report will be provided to the 
sites to register the data obtained. 
In case of abnormal result or sudden increase, a repeated measurement will be required 4 weeks later (to 
be performed at an unscheduled visit). 


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Recommended values for different stage of fibrosis are described in Table 3. 
Table 3: 
Recommended values for fibrosis staging 
 
F0-F1(kPa) 
F2(kPa) 
F3(kPa) 
F4(kPa) 
NAFLD/NASH 
≤7.0 
≥7.5 
≤10 
≥14.0 
Abbreviations: kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic 
steatohepatitis 
If at baseline, the measurement gives an abnormal value (i.e., ≥14 kPa) but without being associated with 
confirmed histological cirrhosis, a FibroScan measurement will be continued as planned in the protocol but 
will not be used for the detection of cirrhosis. 
6.2.5. 
Quality of life questionnaire 
A standardized and validated questionnaire for quality of life (SF-36) will be completed by patients at V1, 
V3, V5, and V7 in the First Treatment Period, and V8, V9, V11, and 48 weekly thereafter in the Long-term 
Treatment Period until, and including the EOT Visit. 
6.3. 
IMPORTANT 
SPECIFIC 
BIOLOGICAL 
CONSIDERATIONS 
AND 
PATIENT 
DISCONTINUATION RULES 
6.3.1. 
Creatine phosphokinase 
If at any visit during the treatment periods, a patient experiences diffuse myalgia, muscle tenderness, 
and/or marked increase in muscle CPK values comprised between 3 x and 5 x ULN, an additional visit and 
test within 3 to 7 days must be performed. If, during that visit, the patient still experiences diffuse myalgia, 
muscle tenderness and/or marked increase in muscle CPK values between 3 x and 5 x ULN, myopathy 
must be considered and the patient must be discontinued from study treatment immediately and followed 
up as described in Section 5.2.2. 
If at any visit during the treatment periods, a patient experiences marked increase in muscle CPK values 
>5 x ULN, the patient must be discontinued from study treatment immediately and followed up as 
described in Section 5.2.2. 
6.3.2. 
Liver function monitoring 
All liver decompensation events included in the composite efficacy endpoint (Section 1.9.2) will be 
adjudicated by the Clinical Events Committee (CEC; see Section 6.5), as well as all DILI events (see 
Section 6.5). 


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For DILI adjudication, assessment may be performed using as baseline value the average obtained from 
measurements at the SV1 and V1 visits (described in the CEC manual). 
6.3.2.1. 
Monitoring of patients with normal baseline aminotransferase values 
Liver function monitoring requirements for patients with normal baseline aminotransferase (AT) values at 
V1 who at any visit from V2 onwards during the treatment periods exhibit: 
• 
Increase in AT to <3 x ULN: no additional action required, schedule next visit as per assessment 
schedule 
• 
Increase in AT to >3 x ULN but <5 ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o 
AT remains >3 x ULN but <5 x ULN: continue the drug with close serial monitoring (once 
a week) 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT Visit (see Section 3.9 and Section 5.2.2). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule EOT 
Visit (see Section 3.9 and Section 5.2.2) 
o 
AT reduces to <5 x ULN: continue the drug with close serial monitoring (once a week). 
6.3.2.2. 
Monitoring of patients with increased baseline AT values 
Liver function monitoring requirements for patients with increased AT baseline values at V1 who at any 
visit post V1 onwards during the treatment periods exhibit: 
• 
Increase in AT to <3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule 
• 
Increase in AT to >3 x baseline value but less than 10 x ULN: retest after 48 to 72 hours 
o 
AT remains >3 x baseline value but < 10 x ULN: continue the drug with close serial 
monitoring (once a week) 
o 
AT increases > 5 x baseline value or >10 x ULN: permanently discontinue patient from 
study drug and schedule EOT Visit (see Section 3.9 and Section 5.2.2). 
6.3.2.3. 
Monitoring of all patients 
Patients will permanently discontinue from study drug (see Section 3.9 and Section 5.2.2) if at any visit 
during the treatment periods they exhibit any of the following: 
• 
Increase in AT (>3 x ULN or baseline value) AND increase in total bilirubin > 2 ULN 
• 
Increase in AT (>3 X ULN or baseline value) AND increase in INR>1.5 


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• 
Increase in AT (>3 X ULN or baseline value) AND fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
6.3.3. 
Threshold for diagnostic of cirrhosis 
A FibroScan and serum markers assessments will be performed every 24 weeks at each visit in the Long-
term Treatment Period. 
In case of FibroScan ≥14 kPa, the examination will be repeated 4 weeks later (at an unscheduled visit). A 
liver biopsy may be considered in order to confirm the diagnosis of cirrhosis, if the repeat FibroScan value 
is confirmed ≥14 kPa, and associated with a platelet count <150 000/mm3 and at least 1 elevated serum 
marker of fibrosis indicative of cirrhosis (NAFLD fibrosis >0.676 score or FIB-4 >2.67). In some instances, 
a fibroscopy may be required before any histological confirmation. In the case of detection of variceal 
rupture at fibroscopy or any cirrhosis related event, such as MELD ≥15, hepatic encephalopathy, or ascites, 
then the liver biopsy will not be required for diagnosis of cirrhosis, but the diagnosed event will have to be 
adjudicated by the CEC. 
If cirrhosis or any event listed in the long-term composite endpoint is diagnosed, the patient will 
discontinue the study drug and the study and will be followed up as described in Section 5.2.2 and 
Section 5.2.3. 
6.4. 
SAFETY DATA REVIEW 
An independent DSMB will be established in order to review the progress of the study and to perform a 
safety data review on a regular basis during the trial to protect patient welfare and preserve study 
integrity. 
The DSMB will consist of at least 4 experienced physicians (1 each of endocrinologist, cardiologist, 
hepatologist, and nephrologist) and 1 statistician, all of whom will be independent of the participants in the 
study. A DSMB Charter will define the role, responsibilities, rules, and tasks of the DSMB. 
6.5. 
CLINICAL EVENT COMMITTEE 
The CEC will specifically assess and adjudicate all disease progression events included in the primary 
composite efficacy long-term endpoint (Section 1.9.2, except for histological cirrhosis), all DILI events, and 
all major cardiovascular events: i.e., cardiovascular death, nonfatal myocardial, infarction and stroke 
events as defined in the CEC manual. The CEC assessment and adjudication will occur in a blinded, 
consistent, and unbiased manner throughout the course of a study to determine whether the endpoints 
meet the protocol-specified criteria. 
The CEC will comprise 2 hepatologists, and 1 cardiologist, all of whom will be independent of the 
participants in the study. 


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6.6. 
GUIDANCE FOR INVESTIGATORS 
The safety and tolerability of GFT505 were confirmed in Phase I and Phase II studies. 
A Phase I program to assess the safety and tolerability as well as the PK profile of elafibranor has been 
conducted through 12 clinical trials, 1 of which is still ongoing. A total of 608 volunteers were randomized 
in these studies performed in Phase I centers, including 536 healthy lean subjects, 60 overweight or obese 
subjects, and 12 patients with type 2 diabetes. 
A Phase II program was initiated to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders. To date, 5 Phase IIa pilot trials have been completed in which 
297 patients were randomized. A Phase IIb trial has recently been completed, and evaluated the efficacy 
and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with NASH. 
Of the 65 SAEs that have been reported cumulatively in the clinical development program, 44 occurred 
with elafibranor, 13 with placebo, and 8 prior to administration of study medication. 
Of the 44 SAEs that occurred with elafibranor, only 9 were considered as having a reasonable possibility of 
relationship to elafibranor by the Investigators (serious adverse reaction). They consisted of: 
• 
Atrial fibrillation in a patient with history of arterial hypertension and suspected chronic coronary 
disease with elafibranor 80 mg 
• 
Acute cholecystitis & acute pancreatitis that occurred in a patient on the second day of drug 
administration with elafibranor 80 mg 
• 
Spontaneous abortion in a pregnant patient treated for 6 months with elafibranor 80 mg 
• 
Ataxia, tremor and fasciculations in a patient treated for 51 weeks with elafibranor 80 mg 
• 
Acute pancreatitis that occurred after 7 weeks of treatment in a patient treated with elafibranor 
120 mg 
• 
Parkinson’s disease in a patient treated for 12 months with elafibranor 120 mg, aged 76 years, so 
in the risk group for Parkinson’s disease, and with a family history of Parkinson’s disease. 
For 3 of the SAEs (atrial fibrillation, acute cholecysto-pancreatitis, and Parkinson’s disease) after later 
investigations, and given the medical history of the patients or the time of occurrence of the event, a 
relationship to elafibranor was deemed excluded by the Sponsor. 
All adverse reactions (AEs reported by Investigators as possibly related or related to study drug) reported 
in more than 1% of patients treated with elafibranor in clinical studies with repeated doses of at least 
80 mg elafibranor per day are summarized in Table 4. 


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Table 4: 
Common non-serious adverse reactions (>1% of patients treated with GFT505) 
by system organ class reported in completed elafibranor clinical studies with repeated 
administration of elafibranor (at least 14 days) from 80 mg/d up to 300 mg/d (maximum 
tolerated dose) 
System Organ Class 
Adverse Reaction 
Severity 
Frequency 
Gastrointestinal 
disorders 
Nausea 
Mild to severe 
4.4% 
Diarrhea 
Mild to moderate 
3.1% 
Vomiting 
Mild to moderate 
1.7% 
General disorders and 
administration site 
conditions 
Fatigue 
Mild to moderate 
2.0% 
Asthenia 
Mild to moderate 
1.1% 
Musculoskeletal and 
connective tissue 
disorders 
Myalgia 
Mild to severe 
3.1% 
Investigations 
Hepatic enzymes 
increased 
(mainly transaminases) 
Mild to severe 
1.8% 
Blood creatine 
phosphokinase 
increased 
Mild to moderate 
1.1% 
Metabolism & nutrition 
disorders 
Decrease appetite 
Mild to severe 
1.7% 
Renal and urinary 
disorders 
Renal failure/impairment 
Mild to moderate 
1.3% 
Skin and subcutaneous 
tissue disorders 
Rash 
Mild to moderate 
1.3% 
Vascular disorders 
Hot flush 
Mild to moderate 
1.3% 
 
Among the non-serious adverse reactions, the most frequent were gastrointestinal disorders and general 
disorders. The first ones consisted mostly of nausea, diarrhea, and vomiting. For general disorders, the 
main symptoms were fatigue or asthenia. Myalgia was also frequently reported. These are considered 
common and expected. 
Other non-serious adverse reactions reported in more than 1% of patients concerned changes in biological 
parameters such as liver enzymes increase (mainly transaminases), CPK elevation, or increase of creatinine 
(reported by Investigators as renal failure and/or impairment due to the calculation of creatinine clearance 
by MDRD based on creatinine). Decrease of appetite, rash and hot flush were also reported in more than 
1% of patients but remain limited. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
trials, given the known effects of PPARalpha agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical trials. For this reason, it is recommended that Investigators review these lab results in 
the course of clinical trials. 


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Other known effects of PPARalpha agonists include the increase of creatinine, which was observed in our 
phase IIa and IIb trials, in a range of 5-10%. This increase was reversible at end of treatment. This should 
also be monitored in clinical trials. 
Liver enzymes will also be monitored in clinical trials, with specific attention paid to DILI. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, and 
in the absence of human pregnancy data, GFT505 may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation Group 
(CTFG) document Recommendations related to contraception and pregnancy testing in clinical trials 
(September 2014). 
As such, all clinical trials with GFT505 including women of childbearing potential request a negative 
pregnancy test before Randomization, with effective contraceptive measures throughout the study. It is 
recommended to maintain the contraception up to 1 month after end of treatment. Pregnancy tests should 
be repeated as stated in each study protocol. In the absence of a clinical pharmacokinetic interaction study 
between GFT505 and contraceptive steroids, the exclusive use of hormonal contraceptive methods during 
clinical trials should be avoided, and they should be accompanied by barrier methods. 
Conclusion 
Based on the cumulative experience gathered to date, gastrointestinal disorders such as nausea, diarrhea, 
and vomiting, asthenia or fatigue, myalgia are considered common and expected adverse reactions 
reasonably associated with GFT505. Most of them are of mild to moderate intensity. As previously, 
laboratory increases of serum creatinine or CPK should be monitored throughout clinical trials as this has 
been observed in Phase II trials, and is a known PPARalpha agonist effect. Elevation of transaminases will 
be monitored as well as drug-induced liver injury. In the absence of human pregnancy data, double 
contraception should be maintained for women of childbearing potential participating in clinical trials with 
GFT505 treatment, up to 1 month after end of study treatment. 
 


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7. 
TREATMENTS 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS 
Elafibranor (Propanoic acid, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1(E)-propenyl] phenoxy]-2-
methylpropanoic acid) will be supplied as 120 mg white to off-white round coated tablets with no printed 
inscription. The tablet contains elafibranor and inactive ingredients 
 
 
Placebo to match elafibranor 120 mg will be provided as a white to off-white round coated tablet with no 
printed inscription. 
Standard diet and exercise recommendations (see Section 5.1.1 and APPENDIX II: Adequate diet and 
lifestyle recommendations) will be given at the beginning of each patient’s participation and will be 
maintained throughout the study. 
For additional information see Investigator’s Brochure. 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 8 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 4 blisters. Three wallets will be packaged inside a carton. 
7.2.2. 
Labeling 
All labels for study drugs meet all applicable requirements of the US Food and Drug Administration (FDA) 
and the EU annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal Products 
(July 2003) and /or other local regulations, as applicable. 
Distribution of study drug will be performed according to the Good Distribution Practices. 
Product cartons will be labeled with the protocol number, Sponsor’s name and address, description of 
contents, storage conditions, expiry date, dosage instructions, and any other applicable items required by 
national and regional guidelines/regulations. The label will contain the statements “For clinical trial use 
only” or other similar/appropriate statements as well as the following instructions “Please return empty 


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packaging and unused products to your doctor at your next visit.” Details of carton and wallet labels are 
detailed in APPENDIX V: PRODUCT CARTON AND WALLET LABELING. 
7.2.3. 
Dosage and administration of Elafibranor and placebo 
Patients will be informed to take one tablet per day of elafibranor 120 mg or placebo orally before 
breakfast with a glass of water each morning. 
7.2.4. 
Prior and concomitant medications 
All concomitant medications will be recorded in the source documents and eCRF. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study. 
Upon screening of the first patient, the system will immediately forward the information to the Drug 
Distribution Center which will be responsible to send one of several blocks of treatment packages 
(containing 96 tablets to last approximately 3 months) allocated to the site. The pharmacy will 
acknowledge receipt of the study drug in the IXRS. 
An e-mail, confirming that the patient has been screened, will be sent to the Investigator, 
 and to 
the Sponsor. 
After having received the liver biopsy results as well as the SV1 laboratory results (SB1) (or when 
applicable, results of any retesting performed), and if the patient fulfills all criteria to enter the treatment 
period, the Investigator will register the patient in the IXRS to randomize him/her. 
The IXRS will check if the Investigator is authorized to use the system (identification number and access 
code) and will ask some questions to check the patient eligibility. The IXRS will then allocate the patient to 
a treatment group (elafibranor 120 mg or placebo) through a patient number (with 7 digits), as described 
in Section 3.2. 
A specific IXRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IXRS partner and will be kept in blinding condition to the 
study participants until the Blind-Review Meeting and the Sponsor authorization to unblind the trial. 
7.3. 
STORAGE CONDITIONS 
Elafibranor and placebo should be stored between +15°C and +25°C (59°F and 77°F). Storage conditions 
are specified on the label. 
7.4. 
DISPENSING OF TREATMENT 
Each site will have a resupply strategy within the IXRS (as defined in the Drug Shipment Details document) 
to determine the supply of study drugs sent to each site. Initial site shipments will be shipped at a static 


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value defined in the supply strategy. Following Randomization of a patient IXRS will project for the amount 
of study drug required for future visits and ensure the study drug is at site for the visits occurring. The 
IXRS will continue to project study drug requirements per patient until an event occurs which stops the 
projections for that patient. 
The Investigator will register the patient’s visit in the IXRS who will allocate to the patient a treatment 
package for approximately 3 months (96 tablets) in the First Treatment Period and for approximately 
6 months (192 tablets) in the Long-term Treatment Period. An e-mail, confirming the registration, will be 
sent to the Investigator and to the Sponsor. 
The treatment package will include a carton with 3 wallets of 4 blisters for the First Treatment Period and 
2 cartons with 3 wallets of 4 blisters in the Long-term Treatment Period. 
Each randomized patient will be given, from V1 and at every following visit, the study medication 
containing the adequate number of wallets to cover the drug administration for the period between visits. 
The time between visits will be 12 weeks ± 1 week (to a maximum of 96 days) during the First Treatment 
Period and 24 weeks ± 2 weeks (to a maximum of 192 days) between visits in the Long-term Treatment 
Period, which correspond to the number of tablets provided to the patient at each visit. 
7.5. 
TREATMENT REPLACEMENT 
A specific IXRS procedure manual will be provided to the Investigator and will detail the procedure in case 
of need of treatment replacement. 
7.6. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. 
Identification numbers will be assigned to a patient at the Screening Visit. The number will also be 
reported in the eCRF. Upon completion of the Screening visit(s), eligible patients will be randomly assigned 
to active treatment (elafibranor 120 mg) or placebo at the first visit of the First Treatment Period (V1). 
7.7. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the clinical 
management of the patient. For each patient, the list of treatment numbers allocated to the patient will be 
stored in the IXRS. The Investigator will be able to unblind any treatment box that was dispensed to the 
patient by connecting the IXRS (24-hour & 7-day access) and entering their identification number and 
access code. A back-up phone Interactive Response Technology (IRT) module will also be available should 
the site be unable to access the internet. The IXRS will verify the authorization to unblind the entered 
treatment box and the screen will then display the treatment group, when completed, a blinded 
confirmatory e-mail will be sent to the Investigator and the Sponsor. 


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The reason for unblinding should be clearly and fully documented by the Investigator. 
7.8. 
STUDY DRUG COMPLIANCE 
From V2 and at every following visit while the patient is being treated with study drug, the patient will be 
directed to bring back all used and unused boxes and blisters. Compliance will be checked by the 
Investigator during those visits and registered in the eCRF. 
If treatment is interrupt, whatever the cause, duration and reason of the interruption should be 
documented. 
7.9. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. 
The Investigator or pharmacist will sign a receipt for each study treatment on the day of receipt. A drug 
accountability record should be maintained by the person responsible for dispensing the trial medication to 
the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion of 
the study. 
On Sponsor request, the Drug Distribution Center will organize the retrieval of all treatments (used or 
unused) and will proceed to their destruction only after the Sponsor provides written authorization. 
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site may 
destroy used and unused study drugs in accordance with the site SOP and always after the drug 
accountability has been performed by the monitor. 
If drug is destroyed in the site, the Investigator must maintain accurate records for blisters destroyed 
recording: 
• 
Blister identification 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed the drug. 
 
7.10. OTHER MEDICATION 
7.10.1. 
Handling of concomitant medication 
In a general manner, patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. In the same way, any 
qualitative or quantitative change in concomitant therapy should be avoided, when possible. 


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In the event that it becomes necessary during the study, this should be recorded by the Investigator in the 
eCRF and information should be communicated to the Medical Monitor in order to evaluate the risk of 
DDIs. This includes drugs used on a chronic as well as on an “as needed” basis. 
7.10.2. 
Non-permitted medication 
The following medications are not allowed within the timeframe given in APPENDIX III: 
Permitted/Non-permitted medication): 
• 
Glitazones (pioglitazone & rosiglitazone) 
• 
Fibrates 
• 
Corticosteroids (parenteral & oral chronic administration only) 
• 
Amiodarone 
• 
Tamoxifen 
• 
Methotrexate 
• 
Indomethacin. 
The following medication is not allowed to be initiated during the treatment periods of the study (see 
APPENDIX III: Permitted/Non-permitted medication): 
• 
GLP-1 agonist. 
If it is identified after Randomization that these non-permitted drugs have been administered to a patient 
within the excluded timeframes, the patient will be permanently discontinued from the study drug (see 
Section 5.2.2). 
7.10.3. 
Permitted 
medication 
under 
condition 
(see 
APPENDIX 
III: 
Permitted/Non-permitted medication) 
• 
The following medications are permitted under the condition of steady dosage prior to Screening: 
o 
statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
 
• 
The following medications are permitted under the condition of stable dose from at least 6 months 
prior to diagnostic liver biopsy: 
o 
vitamin E >400 IU/day 
o 
PUFAs >2 g/day 
o 
ursodeoxycholic acid 
o 
GLP-1 agonist. 


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Importantly, no initiation of GLP-1 agonists will be allowed during the treatment periods of the study. 
Should the Investigator decide to initiate this drug, it would lead to permanent discontinuation of the 
patient from the study drug (see Section 5.2.2). 
• 
The following medications are permitted under the condition of no qualitative change (i.e., 
implementation of a new antidiabetic drug) in the 6 months prior to diagnostic liver biopsy: 
o 
insulin 
o 
sulfonylurea medications 
o 
metformin 
o 
gliptins 
o 
SGLT2-inhibitors. 
Patients on sulfonylurea medications and insulin are recommended to self-monitor blood glucose. 
7.10.4. 
Permitted medication 
Any medications other than those listed above are permitted. However, the dosage of a current medication 
for a chronic disease should remain unchanged as far as possible in order to reduce the risk of unknown 
DDIs. 
In the event that additional concomitant therapy becomes necessary during the study, this should be 
recorded by the Investigator in the eCRF. This includes drugs used on a chronic as well as on an 
“as-needed” basis. Patients should be discouraged from starting any new medication without consulting 
the Investigator unless the new medication is required for emergency purpose. 
 
 


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8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT 
8.1. 
DEFINITIONS 
8.1.1. 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical (investigational) product and which does not necessarily have to have a causal relationship 
with this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding or 
physiological observation, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal product. 
Examples of AE include (but are not limited to): abnormal test findings; clinically significant symptoms and 
signs; changes in physical examination findings; hypersensitivity; progression/worsening of pre-existing 
condition or underlying disease; recurrence of a pre-existing condition; lack of effect, complication, and 
termination of pregnancy. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug withdrawal, drug 
abuse, drug misuse, drug interactions, drug dependency, extravasation, exposure in utero. 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms 
• 
Test result requires additional diagnostic testing or medical/surgical intervention 
• 
Test result leads to a change in trial dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an AE. Any 
abnormal test result that is determined to be an error does not require reporting as an AE. 
An AE does not include the following: 
• 
Medical or surgical procedures performed; the condition that leads to the procedure may be an AE 
if applicable 
• 
Pre-existing disease, condition or laboratory abnormalities present or detected before the 
Screening Visit that do not worsen 
• 
Overdose without clinical sequelae 


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• 
Any medical condition, or clinically significant laboratory abnormality with an onset before the 
consent form is signed. Such as medical condition is considered to be pre-existing and should be 
documented on the medical history of the eCRF 
• 
Uncomplicated pregnancy 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
• 
Events that are identified as efficacy endpoints for the long-term evaluation (described in 
Section 1.9.2) should not be reported as AE. For more details on endpoint reporting, please refer 
to the CEC Manual. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when the 
active phase of the study begins and is not a chronic condition that is part of the patient’s medical history, 
or (2) it is present at the start of the active phase of the study or as part of the patient’s medical history, 
but the severity or frequency increases during the active phase. The active phase of the study begins at 
the time of the first dose of the study drug. The active phase of the study ends at the follow-up visit. 
8.1.2. 
Serious adverse events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (see Section 8.1.2.1) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (see Section 8.1.2.2) 
• 
Results in persistent or significant disability/incapacity (see Section 8.1.2.3) 
• 
Is a congenital anomaly/birth defect (including fetal malformations associated with spontaneous 
abortions or elective abortions) 
• 
Is another medically important condition (see Section 8.1.2.4). 
In addition, any illnesses reported before starting active treatment or AE meeting the criteria of 
seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g., wash-out period, laboratory testing procedure) must be reported as an SAE. 
8.1.2.1. 
Life-threatening adverse events 
A life-threatening AE in the definition of "serious" refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 


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8.1.2.2. 
Inpatient or prolonged hospitalization 
An inpatient hospitalization or prolongation of a hospitalization means that the patient stays overnight in 
the hospital. Pre-planned hospital stays or hospital stays for nonmedical social reasons will not be 
considered as hospitalization, for example: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
considered serious. 
• 
Hospitalization or prolongation of hospitalization is part of a routine procedure followed by the 
study center (e.g., stent removal after surgery). This should be recorded in the study file. 
• 
Hospitalization for survey visits or annual physicals fall in the same category. 
• 
Hospitalization planned before the start of the study for a pre-existing condition that has not 
worsened does not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a pre-existing condition of osteoarthritis of the knee that has not worsened during the 
study). 
8.1.2.3. 
Significant or incapacitating disability 
Only a persistent or significant or incapacitating disability is intended. This item refers to a substantial 
disruption of a person’s ability to conduct normal life functions. Thus, disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma. 
8.1.2.4. 
Medically important conditions 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should usually be considered serious. 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse. 
8.1.3. 
Clarification on serious adverse events: 
• 
As an outcome event, progression to cirrhosis should not be included as AE. 
• 
Death is an outcome of an AE, not an AE in itself. 


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• 
An SAE may occur even if the patient was not being treated with the investigational medicinal 
product at the occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death. This does not include an event 
that might have led to death if it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE. 
• 
Patient hospitalization means that the patient stays overnight in the hospital. Pre-planned hospital 
stays or hospital stays for nonmedical social reasons will not be considered as hospitalization. 
• 
A procedure for protocol/disease-related investigations (e.g., biopsy) should not be reported as 
SAE. Hospitalization or prolonged hospitalization for a complication of such procedures should be 
reported as SAE. 
8.1.4. 
Adverse drug reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended and that is considered casually related to an investigational medicinal product. A serious ADR 
(SADR) is an ADR which meets the seriousness criteria. 
8.1.5. 
Unexpected adverse event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature of 
severity or specificity that is not consistent with the applicable Investigator Brochure or that is 
symptomatically and pathophysiological related to a known toxicity but differs because of a greater severity 
or specificity. 
“Unexpected” refers to an ADR that has not been previously observed and reported rather than an event 
that has not been anticipated based on the properties of the drug. 
8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AE have occurred at each visit from the date of consent. 
The patient will be questioned in a general manner to determine specific symptoms without offering the 
patient any suggestion. 
8.2.1. 
Intensity assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing 
no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; 
signs and symptoms are transient. 


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• 
Moderate: Events introduce a low level of inconvenience or concern to the participant and may 
interfere with daily activities, but are usually improved by simple therapeutic measures; moderate 
experiences may cause some interference with functioning. 
• 
Severe: Events interrupt the participant’s normal daily activities and generally require systemic 
drug therapy or other treatment; they are usually incapacitating. 
8.2.2. 
Relation to the study treatment 
The Investigator will make a clinical and scientific judgment regarding whether or not the AE was related 
to study treatment. The Investigator will evaluate any changes in laboratory values, make a determination 
as to whether or not the change is clinically important, and whether or not the changes were related to 
study drug. However, even if the Investigator feels there is no relationship to the study drug, the AE or 
clinically significant laboratory abnormality must be recorded in the eCRF. 
The Investigator will record the relation to the study treatment according to the following causality terms: 
• 
Related: the AE follows a reasonable temporal sequence from the time of drug administration 
and it cannot be explained by the patient's clinical state or the study procedures/conditions. The 
AE abates upon discontinuation of the study drug and reappears when the study drug is 
introduced. 
• 
Possibly related: the AE follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by the patient's clinical state or the study 
procedures/conditions. 
• 
Unlikely related: the temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. The relationship is not 
likely because of other plausible explanations. 
• 
Not related: the AE must definitely be caused by the patient's clinical state or the study 
procedure/conditions. A reasonable explanation must be given, e.g., no investigational product 
taken, preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action taken and outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according to 
the following: 
Action taken with investigational drug 
• 
Drug permanently withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug temporarily withdrawn – in case the study drug is temporarily withdrawn 
• 
Dose not changed – in case no action is taken regarding the study drug 


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• 
Unknown 
• 
Not applicable – an AE started before initiation of treatment with study drug, the treatment had 
been completed prior to reaction/event, or the patient has died. 
Outcome 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered/resolved with sequelae 
• 
Fatal 
• 
Unknown. 
Note: In case of irreversible congenital anomalies the choice not recovered/not resolved should be used. 
“Fatal” should be used when death is possibly related to the reaction/event. 
8.3. 
REPORTING 
8.3.1. 
Reporting an adverse event 
All AEs regardless of seriousness or relationship to study drug, including those occurring during the 
Screening Period, are to be recorded on the corresponding page(s) of the eCRF and in the patient’s 
medical record from the ICF signature until the final follow-up visit. Whenever possible, symptoms should 
be grouped as a single syndrome or diagnosis. The Investigator should specify the date of onset, maximal 
intensity, action taken with respect to study drug, corrective therapy given, outcome, and his/her opinion 
as to whether there is a reasonable possibility that the AE was caused by the study drug. 
Adverse event reporting begins from signature of the patient ICF at the first Screening Visit and ends at 
the last study visit. 
8.3.2. 
Reporting a serious adverse event 
Serious AE reporting begins from signature of the patient ICF and ends at the last study visit. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported 
Events that are identified as potential efficacy endpoints for long-term evaluation will NOT be reported as 
SAEs unless it is determined by the adjudication committee that the event does not meet the predefined 
criteria for an endpoint. Events that are identified as potential efficacy endpoints for long-term evaluation 
that are not confirmed by adjudication will be reported as described with the start of the reporting time 
window being the time of negative adjudication decision. 


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Investigators must notify, by fax or e-mail, the Sponsor designated representative 
 
 of all SAEs IMMEDIATELY (within 24 hours of the Investigator 
becoming aware of the event). 
ANY SERIOUS ADVERSE EVENTS, WHETHER OR NOT RELATED TO THE STUDY DRUG, MUST BE 
REPORTED IMMEDIATELY (WITHIN 24 HOURS) TO 
 AT THE 
FOLLOWING FAX NUMBERS: 
FAX numbers: 
 
Contact Person: 
 
E-mail: 
 
All SAEs independent of the circumstances or suspected cause must be reported in ENGLISH on a SAE 
Form. The SAE Form should include a clearly written narrative describing signs, symptoms, and treatment 
of the event, diagnostic procedures, as well as any relevant laboratory data and any sequelae, in order to 
allow a complete medical assessment of the case and independent determination of the possible causality. 
The Investigator is also required to submit follow-up SAE reports to 
 within 
24 hours of becoming aware of additional information such as diagnosis, outcome, causality assessment, 
results of specific investigations, and any new significant information that has not been previously 
reported. 
It is critical that the information provided on the initial or follow-up SAE Form matches the information 
recorded in the source documents and the eCRF for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case reports, 
autopsy reports, and other documents should be sent when requested and applicable. All provided reports 
must be anonymized. 
Follow-up reports relative to the patient’s subsequent course must be submitted to 
 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
The Sponsor or its designated representative will report all the relevant safety information to the 
concerned Competent Authorities and to the Independent Ethics Committee(s) (IRB/IEC) concerned 
according to the country-specific requirements. 
Investigator must fulfill his/her regulatory obligations to the Regulatory Authorities and/or to the Ethics 
Committee in accordance with local regulations. 
Depending on local regulations in different regions and countries, the Sponsor or designated clinical 
research organization (CRO) may be required to expedite report to the Regulatory Authorities for: 


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• 
SAEs (including events related to study procedures) 
• 
SADRs 
• 
Suspected unexpected serious adverse reactions (SUSARs) 
Each SAE report received from the Investigators will be evaluated by the designated CRO for 
pharmacovigilance who will assess the seriousness of the event. Each SAE report will be evaluated by the 
Sponsor and/or his designees who will assess the relationship to study procedure or study treatment and 
the expectedness of the event. Expectedness will be assessed using the reference safety information 
included in the Investigator Brochure. 
Any unexpected safety issue that changes the risks benefit analysis and is likely to have an impact on the 
patients who have participated in it will be reported by the Sponsor as soon as possible to the Competent 
Authority(ies) concerned together with proposed actions. 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she 
should follow up the outcome of any AE until the return to normal or until consolidation of the patient 
condition. 
The patient must be followed up until clinical recovery is complete and laboratory results have returned to 
normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor. This 
information should be documented in the patient’s medical records. 
8.4. 
POST STUDY REPORTING REQUIREMENTS 
Any SAEs and deaths that occur within 30 days of the last dose of the study drug, regardless of causality, 
should also be reported. 
Any SAE that is brought to the attention of the Investigator at any time after the reporting period and 
which is considered by him/her to be caused by the study drug within a reasonable possibility, should be 
reported. 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS 
Laboratory abnormalities are not necessarily recorded as AEs or SAEs. However, laboratory abnormalities 
that are considered clinically relevant by the Investigator must be recorded as an AE or SAE as applicable. 


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8.6. 
SPECIAL SITUATION REPORTS 
Special situations reports include pregnancy reports, reports of medication error, abuse, misuse or 
overdose, and reports associated with product complaints. 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to 
 by faxing 
a completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study medication should also be reported to 
 using the corresponding pregnancy form. 
Female patients must be instructed to discontinue the study drug immediately and inform the Investigator 
as soon as possible once they are aware of being pregnant or suspect that they are pregnant during the 
study or within 30 days of the last dose of the study drug. 
Female patients will be requested, as part of the general ICF, to provide informed consent to allow 
reasonable attempts to be made to obtain information on any possible medicinal product exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome of 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs as detailed in Section 8.3.2. 
The pregnancy itself is not considered an AE. 
8.6.2. 
Medication error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient, or consumer. All medication 
errors will be documented in the eCRF and, in case of any potential risk to patient safety, would be 
reported as appropriate (see Section 8.3). 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information and will be reported in the eCRF. All misuse will be 
documented in the eCRF and, in case of any potential risk to patient safety, would be reported as 
appropriate (see Section 8.3). 


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8.6.4. 
Overdose 
This refers to the administration of a quantity of a medicinal product given per administration or 
cumulatively, which is above the maximum recommended dose according to the authorized product 
information (see Section 8.1.1 and Section 8.3.1). Clinical judgment should always be applied. 
8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is 
accompanied by harmful physical or psychological effects. 


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9. 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details on 
statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This SAP 
may be revised during the study only to accommodate protocol amendments and to make changes to 
adapt to unexpected issues in study execution and data collection that could affect planned analyses. In all 
circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The first 
approved version of the SAP should be available within 3 months of protocol submission and before the 
first DSMB meeting. 
The main analyses will be based on patients with fibrosis stage F2 and F3. The summaries will be repeated 
in an exploratory manner with the inclusion of patients with fibrosis stage F1. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
• 
Type 2 diabetes (yes, no) 
• 
Gender (male, female) (with a capping of women to 40%) 
• 
Fibrosis stage (F1, F2, F3) (capped to 202 F1 patients). 
Details on the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. 
Surrogate endpoint - resolution of NASH 
The first surrogate endpoint for this study is resolution of NASH without worsening of fibrosis after 
72 weeks of treatment with elafibranor. Resolution of NASH is defined as the disappearance of ballooning 
(i.e., grade 0) and disappearance or persistence of minimal lobular inflammation (i.e., grade 0 or 1) with 
an overall pattern of injury not qualifying for steatohepatitis. Worsening of fibrosis is evaluated using NASH 
CRN fibrosis staging system and defined as progression of at least 1 stage. This surrogate endpoint will be 
formally assessed at the time of the interim analysis when approximately 50% (at least 1023) of the F2 to 
F3 patients complete the 72 week treatment period or discontinue early from the study (see Section 9.8.1 
for details. An additional exploratory analysis of this endpoint will take place at the time of the final 
analysis. 
9.2.2. 
Long-term endpoint – time to clinical event/death 
To evaluate the efficacy of elafibranor on clinical outcomes described as a composite endpoint composed 
of death to any cause, liver cirrhosis and the full list of portal hypertension/cirrhosis related events: 


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• 
Liver transplantation 
• 
MELD score ≥15 
• 
HCC 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
o 
variceal bleed 
o 
hepatic encephalopathy 
o 
spontaneous bacterial peritonitis 
o 
uncontrolled ascites 
o 
hepatorenal syndrome 
o 
hepatopulmonary syndrome 
o 
chronic gastrointestinal blood loss due to portal hypertensive gastropathy (provided that 
these lead to hospitalization or transfusion). 
The final analysis will be performed when 456 patients experience an event listed above. This is expected 
to occur approximately 72 months after the first patient is randomized. 
9.2.3. 
Key secondary endpoint 
The key secondary endpoint is: 
• 
Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN 
scoring at 72 weeks. 
This key secondary endpoint will be assessed at the time of the interim analysis (on approximately 50% of 
the patients) for the resolution of NASH without worsening of fibrosis endpoint. 
9.2.4. 
Other secondary endpoints 
The other secondary endpoints are: 
• 
To assess histological changes after 72 weeks of treatment and follow-up biopsy on the following 
parameters: 
o 
percentage of patients with resolution of NASH without worsening of fibrosis (follow-up 
biopsy) 
o 
percentage of patients with improvement of fibrosis of at least 1 stage according to NASH 
CRN scoring 
o 
percentage of patients with at least 1 point improvement in histological scores (NASH CRN 
scoring: total NAS, steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD 
Ishak scoring system), or portal inflammation 
o 
percentage of patients improvement of NAS score of at least 2 points 
o 
percentage of patients with at least a 1 point improvement in SAF activity score 


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o 
mean changes in NAS score, fibrosis, steatosis, hepatic ballooning, lobular inflammation, 
portal inflammation, SAF activity score 
o 
changes in area of fibrosis by morphometry 
o 
mean changes in fibrosis using NASH CRN and NAFLD Ishak scoring. 
• 
To assess the following endpoints in elafibranor treated patients relative to placebo, at Week 72 
and at the end of the Long-term Treatment Period: 
o 
cardiovascular events 
o 
liver-related death events 
o 
changes in liver enzymes and liver markers 
o 
changes in noninvasive markers of fibrosis and steatosis 
o 
changes in lipid parameters 
o 
variation in body weight 
o 
changes in insulin resistance and glucose homeostasis markers 
o 
changes in inflammatory markers 
o 
changes in cardiovascular risk profile as assessed by Framingham scores 
o 
changes in quality of life (SF-36 questionnaire). 
• 
Time to first occurrence of: 
o 
liver cirrhosis 
o 
death of any cause 
o 
any portal hypertension or cirrhosis related events. 
9.2.5. 
Exploratory endpoints 
The exploratory endpoints are: 
• 
To determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 after 72 weeks of 
treatment for PK population analyses. 
• 
To constitute a biobank for discovery and validation of biomarkers in NASH. 
Details on all endpoints will be given in the SAP. 
9.3. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Enrolled: all patients who sign informed consent. This set will be used to summarize disposition. 
• 
ITT: all randomized F2 and F3 patients. This set will be used to summarize efficacy. The main 
analysis of the primary and key secondary endpoints will be based on the ITT. 
• 
Safety set (SS): all randomized F2 and F3 patients who receive at least 1 dose of study drug. This 
set will be used to summarize safety. 


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• 
Per protocol set (PPS): all F2 and F3 patients who receive at least 1 dose of study drug and do not 
have any important protocol deviations leading to exclusion from the PPS. Important protocol 
deviations will be defined in the SAP and agreed prior to database lock. Supportive analysis of the 
primary and key secondary endpoints will be based on the PPS. 
• 
PK set (PKS): All F2 and F3 patients who have taken at least 1 dose of elafibranor and have 
sufficient plasma concentrations to be able to derive the various PK parameters. 
• 
Exploratory F1 cohort: All randomized F1 patients who have taken at least 1 dose of study drug. 
• 
Full Intent-To-Treat Set (FITT): all randomized patients. 
• 
Full Safety Set (FSS): all randomized patients who receive at least 1 dose of study drug. 
• 
Full PK Set (FPKS): All patients who have taken at least 1 dose of elafibranor and have sufficient 
plasma concentrations to be able to derive the various PK parameters. 
Patients in the ITT, FITT, PPS, and exploratory F1 cohorts (study population and efficacy data) will 
analyzed based on randomized treatment. Patients in the SS, FSS, PKS, FPKS, and exploratory F1 cohorts 
(safety data) will be analyzed based on actual treatment received. 
9.4. 
 ANALYSIS OF PRIMARY ENDPOINTS 
9.4.1. 
Resolution of NASH 
The null hypothesis for resolution of NASH without worsening of fibrosis is that there is no difference in 
response rates between the elafibranor and placebo groups. The alternative hypothesis is that there is a 
difference in response rates between the elafibranor and placebo groups. The null hypothesis will be tested 
at the two-sided 0.01 alpha level. 
The number and percentage of patients with resolution of NASH without worsening of fibrosis at the end of 
the 72 week treatment period will be summarized by treatment group. The main analysis will be performed 
using a logistic regression model, with fixed terms for treatment, type 2 diabetes (yes, no), gender (male, 
female), fibrosis stage (F2, F3) and baseline NAS. The statistical model will be used to calculate the odds 
ratio (elafibranor/placebo) and 95% confidence interval. The main confirmatory analysis will be performed 
when approximately 50% of patients (at least 1023) have completed the 72 week treatment period or 
discontinued from the study. The main analysis will be based on the ITT. Supportive analysis will be based 
on the PPS. 
Patients with missing data for resolution of NASH without worsening of fibrosis will be treated as a 
nonresponder for the main analysis. Additional sensitivity analysis using multiple imputations and a pattern 
mixture model will be performed. Further details will be provided in the SAP. 
9.4.2. 
Long-term endpoints 
The null hypothesis for time to clinical event/death is that there is no difference in the survival distributions 
between the elafibranor and placebo groups. The alternative hypothesis is that there is a difference in the 


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survival distributions between the elafibranor and placebo groups. The null hypothesis will be tested at the 
two-sided 0.04 alpha level. 
The data will be analyzed using a Cox proportional hazards model with fixed terms for treatment, type 2 
diabetes, gender, fibrosis stage, and baseline NAS. The Cox proportional hazards model will be used to 
calculate the hazard ratio (elafibranor/placebo) and 95% confidence interval. This will be performed when 
at least 456 patients experience a clinical event/death. 
The time to clinical event/death will be presented graphically using a Kaplan-Meier curve. The median time 
to first clinical event/death and 95% confidence interval will also be presented for each treatment group. 
Missing data will be censored at the last known date. 
The main analysis will be based on the IIT. Supportive analysis will be based on the PPS. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. 
Key secondary endpoint 
The number and percentage of patients with improvement of fibrosis according to NASH CRN scoring at 
the end of the 72 week treatment period will be summarized separately by treatment group. The data will 
be analyzed using a logistic regression model, with fixed terms for treatment, type 2 diabetes, gender, 
fibrosis stage and baseline NAS. 
The analysis will be performed at the time of the interim analysis when approximately 50% of patients (at 
least 1023) have completed the 72 week treatment period or discontinued from the study. 
The main analysis will be based on the IIT. Supportive analyses will be based on the PPS. 
9.5.2. 
Other secondary endpoints 
All other secondary endpoints will be summarized by treatment group using descriptive statistics. The main 
analysis will be based on the ITT. 
Categorical endpoints will be analyzed using a logistic regression model in the same manner as resolution 
of NASH without worsening of fibrosis. 
Time to event endpoints will be analyzed using the Cox proportional hazard’s model in the same manner as 
time to clinical event/death. 
Continuous endpoints will be analyzed using an Analysis of Covariance (ANCOVA) model with fixed terms 
for treatment, type 2 diabetes, gender, fibrosis stage, and baseline NAS. An unstructured covariance matrix 
will be used for this analysis. The statistical model will be used to calculate the mean treatment difference 
and 95% confidence interval. If the data does not meet the required assumptions for parametric tests, the 


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data will be analyzed using a nonparametric Wilcoxon rank sum test. The median treatment difference and 
95% confidence interval will be calculated using the Hodghes-Lehmann method. 
Further details will be in the SAP. 
9.5.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for selected subgroups, 
including, but not limited to, the following: 
• 
Presence of type 2 diabetes (yes, no) 
• 
Gender (male, female) 
• 
Fibrosis (F2, F3) 
• 
Geographic region (North America, Europe, South America, Rest of World) 
• 
Race (Caucasian, Hispanic, Other) 
• 
Age (<55, ≥55 years). 
Forest plots will be generated for each of these endpoints for patients in the ITT population. 
9.5.4. 
Exploratory analyses 
Additional exploratory analyses of the efficacy data will be performed on the exploratory F1 cohort. 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for this study is two-sided α=0.05. The alpha for the primary endpoints will be split 
20%/80%, with two-sided α=0.01 for resolution of NASH and two-sided α=0.04 for time to clinical 
event/death. The overall type I error for the primary endpoints in this study is two-sided α=0.05. The 
alpha for the primary endpoints will be split 20%/80%, with two-sided α=0.01 for resolution of NASH and 
two-sided α=0.04 for time to clinical event/death. 
A hierarchical gate-keeping strategy will be used to control for multiplicity for the key secondary endpoint. 
If the resolution of NASH without worsening of fibrosis endpoint is statistically significant, the key 
secondary endpoint, improvement of fibrosis according to NASH CRN scoring, will be tested in a 
confirmatory manner with a two-sided α=0.5. 
Statistical testing for all other secondary endpoints will be of exploratory nature. 
As this is a single pivotal study that will be used for a regulatory submission, the consistency of the results 
for the primary and key secondary endpoints will be further explored by population and selected 
subgroups. In addition, different approaches will be applied for dealing with missing data. 


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9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in EAST 6.3. 
9.7.1. 
Resolution of NASH 
The following assumptions were made for the sample size calculation for resolution of NASH: 
• 
α=0.01 two-sided 
• 
Randomized patients with no response assessment at Week 72 will be counted as nonresponders 
• 
Pooled variance 
• 
Randomization ratio of 2:1 (elafibranor: placebo) 
• 
8% response in the control group 
• 
16.5% response in the elafibranor group 
The 8% response rate in the placebo group (calculated as the mean response rate based on the Phase II 
FLINT study35 [subanalysis including only patients with stage 2 and stage 3 fibrosis or stage 1 fibrosis with 
diabetes, obesity or ALT ≥ 60 {associated with fibrosis progression}; placebo response rate 6.5%] and the 
GFT505-212-7 placebo data [11% response rate for patients with any stage fibrosis {F1; F2; F3} and 7% 
response rate for patients with only stage 2 and 3 fibrosis]). The 16.5% response rate in the elafibranor 
group is based on the Phase II GFT505-212-7 elafibranor data (calculated as the mean response rate 
based on a 20% response rate for patients with any stage fibrosis ([F1; F2; F3] and 13% response rate for 
patients with only stage 2 and 3 fibrosis). 
Based on these assumptions, a sample size of 1023 patients provides 90% power to show that elafibranor 
is superior to the placebo with respect to resolution of NASH without worsening of fibrosis. 
9.7.2. 
Time to clinical event/death 
The following assumptions were made for the sample size calculation for time to clinical event/death: 
• 
24 month enrollment (with an 18-month ramp up to as many as 200 patients per month) 
• 
72 month maximum follow-up 
• 
α=0.04 two-sided 
• 
Annual event rate of 7% for the placebo group 
• 
Hazard ratio of 0.75 in favor of the elafibranor group 
• 
4% annual drop-out rate over 72 months 
• 
Randomization ratio of 2:1 (elafibranor: placebo). 
The 7% annual event rate in the placebo group is based on published literature on developing cirrhosis in 
patients with NASH and advanced fibrosis (F2-F3).21,22,23,24,25 The rate of developing cirrhosis was 
estimated to be 7% (based on 8% per year in F3 patients and 6% per year in F2 patients). In a 


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conservative approach, no additional event rate was added for other events than histological cirrhosis or 
cirrhosis decompensation events. An annual clinical event/death rate of 7% was thus defined for the 
composite of both these endpoints. 
There is no long-term randomized clinical trial in a NASH population with moderate and severe liver 
fibrosis. In the 72-week FLINT trial, the total drop-out rate was 6.7%.35 Therefore, we estimate an 
approximate annual drop-out rate of 4%. Based on these assumptions, 456 events are required to provide 
80% power to show that elafibranor is superior to placebo with respect to time to clinical event/death. In 
order to obtain 456 events, at least 2022 patients will be required in the IIT. 
9.8. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will summarized by treatment 
group using descriptive statistics. The main summaries of safety will be based on the SS. Additional safety 
analysis will be based on the FSS and the exploratory F1 cohort. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). An overall summary of AEs will be provided. The number and percentage of patients reporting 
AEs will also be presented by MedDRA System Organ Class and preferred term. The AEs will be 
summarized by worst severity and relationship to study drug. Serious AEs, and AEs leading to 
discontinuation will also be summarized. Narratives will be added for all SAE. 
Clinical laboratory tests (hematology, chemistry, and urinalysis) recorded at each timepoint and change 
from baseline will be summarized by treatment group using descriptive statistics. Clinical laboratory values 
for each parameter will be assigned a classification according to whether the value is lower than, within, or 
higher than the reference range for that parameter. The values will then be summarized using shift tables 
to evaluate categorical changes from baseline to end of the 72 week treatment period with respect to 
reference ranges. The number and percentage of patients reporting markedly abnormal clinical laboratory 
values will also be summarized by treatment group. 
Liver and kidney related laboratory tests including an assessment of DILI will also be summarized. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
using descriptive statistics. The QTc and other ECG parameters recorded at each timepoint and change 
from baseline will also be summarized using descriptive statistics. 
9.8.1. 
Interim analysis 
The analysis of resolution of NASH without worsening of fibrosis will occur when approximately 50% of the 
F2 and F3 patients (i.e., 1023 patients) complete 72 weeks of treatment or discontinue early from the 
study. The null hypothesis will be tested at the two-sided 0.01 alpha level. 


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At this time, a snapshot of the database will be cleaned and locked for analysis and potential Subpart H or 
conditional approval submission. This analysis will be done by an unblinded team separate from the study 
team; the study team will not be unblinded until the final analysis at the end of follow-up. 
The DSMB will also periodically review safety data from the study to ensure the well-being of study 
participants. These safety reviews will be based on reports generated by the SAC and may include select 
efficacy results so that the DSMB can assess the likely benefit-risk profile of elafibranor. These are not 
considered a formal interim analysis, and no type I error adjustments will be done for these reviews. 
Details will be in the DSMB Charter. 
9.9. 
BLINDED REASSESSMENT 
A blinded reassessment of the clinical event rate will be made when all patients have either completed or 
discontinued from the 72 week treatment period. The number of patients enrolled may be increased at this 
time and/or total duration extended. No adjustment will be made to the targeted number of events 
required for the final analysis of the long-term endpoint, so no adjustment for control of type I error should 
be required for this reassessment. 
 
 


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10. DATA HANDLING AND RECORD KEEPING 
10.1. CRF AND SOURCE DOCUMENTS 
A case report form (CRF) is required and should be completed for each screened patient. The completed 
eCRFs are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized Sponsor’s representatives or appropriate regulatory authorities, without written 
permission from the Sponsor. 
The Investigator will ensure that all data are entered promptly, legibly, completely, accurately and conform 
to source documents, in accordance with specific instructions accompanying the eCRFs designed 
specifically for this study. The CRF being used for this study is an electronic CRF that has been fully 
certified as being compliant with the FDA regulations at 21 Code of Federal Regulations (CFR) Part 11. 
All study required patient data generated during the study will be recorded in the eCRF, with the exception 
of SAE forms and SF-36 which will be collected via ePRO. Patients will not be identified by name in the 
eCRF or on any study documents to be collected by the Sponsor (or designee), but will be identified by a 
patient number (patient initials will also be provided in the eCRF). 
The Investigator will review and approve each completed eCRF; the Investigator’s validation serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data entered in 
the eCRF are complete, accurate and authentic. 
Should a correction be made, the corrected information will be recorded in the eCRF by the authorized 
person and explained (if necessary). All corrected data will be tracked through an audit trail. 
It is the Investigator’s obligation to ensure documentation of all relevant data in the patient’s medical file 
(medical history, concomitant diseases, patient identification number, date of informed consent, visit dates, 
administration of study medication, AEs [start and stop dates] and all concomitant medications [start and 
stop dates]). All data recorded in the eCRF will be documented by source data. 
10.2. RETENTION OF RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. 
The Investigator will be provided with a study file, which should be used to file the Investigator Brochure, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
correspondence with the IRB/IEC, Sponsor, and other study-related documents. 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator agrees to 
keep records, including the identity of all participating patients, all original signed ICFs, copies of all eCRFs, 
source documents, and detailed records of treatment disposition. 


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The Investigator must retain the study documentation until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. However these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
hospital records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from the 
trial. The trial records must be transferred to an acceptable designee, such as another Investigator, 
another institution, or to the Sponsor. 
 
 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. QUALITY CONTROL & MONITORING PROCEDURES 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with the 
protocol, Good Clinical Practice (ICH topic E6), applicable regulatory requirements, and the current 
Declaration of Helsinki (APPENDIX I – World Medical Association Declaration of Helsinki) and that valid 
data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well-organized, and easily retrievable data. 
Before enrolling any patients in this study, the Study Monitor will review the protocol, the brochure for 
clinical Investigators, the eCRFs and instructions for their completion and return, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs with the Investigator. In 
addition, the Study Monitor will explain the Investigator’s reporting responsibilities and all applicable 
regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of Sponsor to monitor the study as frequently as the 
Sponsor deems is necessary to determine that data recording and protocol adherence are satisfactory. A 
Study Monitor from 
 Late Stage Development Services will be responsible for monitoring this 
clinical trial. To this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. The eCRFs and related source documents, as well as 
drug accountability will be reviewed in detail by the monitor at each visit, in accordance with relevant SOPs 
and Good Clinical Practice (GCP; ICH topic E6) regulations. This includes results of tests performed as a 
requirement for participation in this study and any other medical records required to confirm information 
contained in the eCRFs, such as past medical history and secondary diagnoses. 
A risk based monitoring strategy will be used for this study. Study monitoring strategy design will be based 
on overall study risk assessment. Individual site monitoring strategy design will be based on individual site 
risk assessment. On site monitoring will focus on source document verification of critical data and source 
document review of critical processes, and will be supported by formal remote site monitoring activities. 
Centralized monitoring activities will review study data to assess changes in individual site risk and to 
identify emerging trends, risks and issues across sites, countries, regions, and the global study. Further 
details can be found in the Monitoring Plan. 
It is essential that the Study Monitor has access to all documents (related to the study and the individual 
participants) at any time these are requested. In turn, the Study Monitor will adhere to all requirements for 
patient confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be expected to 
cooperate with the Study Monitor, to be available during a portion of the Monitoring Visit to answer 
questions, and to provide any missing information. 


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 All monitoring activities will be reported and archived in the Trial Master File. 
11.2. ETHICAL PRINCIPLES 
This protocol complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the World Medical Assemblies (APPENDIX I – World Medical 
Association Declaration of Helsinki), and the GCP guideline. 
This trial also complies with applicable local regulatory requirements and laws of each country in which the 
study is performed, as well as any applicable guidelines. 
11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, the 
Investigator should permit auditing by the Sponsor and inspection by applicable regulatory authorities. The 
Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for 
review, being understood that these personnel will adhere to all requirements for patient confidentiality, 
and as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the patients should be respected during these 
inspections. 
Clinical data associates from the Sponsor’s representative will review the data for completeness and logical 
consistency. Additionally, the clinical data associates will use automated validation programs to help 
identify missing data, selected protocol violations, out of range data, and other data inconsistencies. 
Requests for data clarification or correction will be electronically provided to the investigative site for 
resolution. Clinical data associates will assure that corrections have been applied properly. 


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12. ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US CFR Title 21 Section 56 (21 CFR 56) require that approval must be 
obtained from an Independent Ethics Committee (IRB/IEC) prior to participation of human patients in 
research studies. Prior to the study onset, the protocol, ICF, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to the patient or the 
patient’s legally acceptable representative must be approved by the IRB/IEC. The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/IEC for the protocol’s review and approval. 
Verification of the IRB’s unconditional approval of the protocol and the written ICF statement will be 
transmitted to the Investigator. Documentation of the relevant IRB/IEC approval and of the IRB/IEC 
compliance with GCP guideline will be maintained by the site and will be available for review by the 
Sponsor or its designee or by the authorized members of regulatory agencies. 
The Applicant must supply the Sponsor with written documentation of the initial favorable opinion of the 
clinical research before the start of the trial. 
The study will not commence until favorable opinion has been obtained from the appropriate IRB/IEC. 
If any alterations, others than changes of administrative nature only, are made to the study protocol, a 
formal protocol amendment will be issued. The IRB/IEC will be informed by the Investigator of subsequent 
protocol amendments and of SUSARs. Approval for protocol amendments will be transmitted in writing to 
the Investigator. 
The amendment will not be implemented until IRB/IEC approval, except in cases where immediate 
implementation is necessary to eliminate or prevent imminent hazard to the patients. A protocol change 
intended to eliminate an apparent immediate hazard must be documented in an amendment, reported to 
the IRC/IEC within 5 working days, and submitted to the appropriate regulatory agencies in the required 
time frame. 
If requested, the Investigator will permit audits by the IRB/IEC and regulatory inspections by providing 
direct access to source data/documents. 
The Investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to exceed one 
year) and a Study Progress Report following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 


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12.2. COMPETENT AUTHORITY 
In the same way as for IRB/IEC (see Section 12.1), when required by national regulation, approval from 
Competent Authorities (CA) should be granted before the beginning of the study. If applicable, 
Amendments will also be submitted to CA for approval. 
12.3. PATIENT INFORMATION AND CONSENT 
Written informed consent for the study will be obtained from each patient before protocol-specific 
procedures are carried out. The ICF used by the Investigator for obtaining the patient's Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics committee 
(IRB/IEC). The ICF will be approved (along with the protocol) by the IRB/IEC. 
In the case of any exploratory substudies, specific study documents will be prepared and IRB/IEC and 
authority approvals shall be obtained when applicable. 
The Investigator or a person designated by the Investigator (according to applicable regulatory 
requirements), will explain the nature of the study and the action of the test product. The patients will be 
informed that participation is voluntary and that they can withdraw from the study at any time. In 
accordance with 21 CFR 50, the informed consent process shall be documented by the use of a written ICF 
approved by the designated IRB/IEC and will be signed and personally dated by the patient or by the 
patient’s legally acceptable representative and by the person who conducted the informed consent 
discussion prior to protocol-specific procedures being performed. A separate consent form will be obtained 
for optional genetic and biomarker samples to be stored in the blood bank. 
The Investigator must maintain the original, dated and signed ICF. A copy of the signed ICF must be given 
to the patient. 
12.4. PATIENT CONFIDENTIALITY 
The Sponsor will affirm and uphold the principle of the patient’s right to protection against the invasion of 
privacy. Throughout this study and any subsequent data analyses, all data will be identified only by 
protocol number and patient number. 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 


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The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the CSA. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (end of study EOT Visit) of the last patient 
participating in the research. 
 
 


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13. FINANCING AND INSURANCE 
13.1. FINANCIAL ISSUES 
Financial contracts will be signed between the Sponsor and the Investigator/Institution before initiation of 
the study. 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the trial will be covered by the insurance taken by the Sponsor for this trial, if 
they were to suffer any prejudice as a result of taking part in the trial. 
In general, if a patient is injured as a direct result of the study drug, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the 
patient’s medical insurance, a government program, or other responsible third party. If laws or regulations 
of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall 
comply with such law or regulation. 
The Sponsor certifies to have taken out an insurance policy to cover the financial consequences of its civil 
liability and that of everyone involved in the research, and notably that of the Investigators and their 
colleagues with regard to any accidents or damage concerning the administration of the drug or 
paraclinical examinations directly linked to the performance of the trial. 


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14. STUDY RESULTS AND PUBLICATION POLICY 
14.1. STUDY REPORT 
The final report will be written in ENGLISH upon completion of study and statistical analysis according to 
ICH E3 guideline. The report or part of it must be submitted to relevant authorities if applicable. 
 will prepare an integrated clinical and safety report. Prior to issuing the final CSR, 
 will 
prepare a draft report for approval by the Sponsor. The report will be in accordance with the ICH E3 
Guideline for Industry: Structure and Content of CSRs. The draft report will be submitted for Quality 
Assurance audit, the findings of which will be incorporated into the final version. 
An electronic copy of the final CSR will be made available to the Sponsor. The study report will be provided 
in PDF and MS Word formats unless agreed otherwise by 
 Reports requiring specialized Sponsor 
formats/alternative computer software packages may be possible on request from the Sponsor but may 
involve extra time and cost. Electronic datasets will also be provided to the Sponsor on issuance of the final 
report. 
After review by the Sponsor, a final CSR will be submitted to the Sponsor which incorporates the Sponsor’s 
comments. 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION 
All materials, information (oral or written), and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), including this protocol, the patient CRFs, and the 
Investigator's Brochure, are the exclusive property of the Sponsor and may not be published, given, or 
disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to any 
third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the ethics committee 
(IRB/IEC) and the Competent Authority is expressly permitted, their members having the same obligation 
of confidentiality. 
The Investigator shall consider all information, results, discoveries, records (accumulated, acquired, or 
deduced) in the course of the study, other than that information to be disclosed by law, as confidential and 
shall not disclose any such results, discoveries, or records to any third party without the Sponsor’s prior 
written consent. 
The Sponsor retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this study. Therefore, the Sponsor reserves the right to use the data from the 
present study, either in the form of Case Report Forms (or copies of these), or in the form of a report, with 


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or without comments and with or without analysis, in order to submit them to the Health Authorities of any 
country. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting on 
his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Clinical study will be registered on the open access website http://www.clinicaltrials.gov before the 
screening of the first patient in the study. 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of their 
studies, using only clean, checked, and validated data in order to ensure the accuracy of the results. 
The publication of study results will be agreed between the Sponsor and the Investigators. 
At least 45 days in advance of proposed submission, the Investigator should forward a copy of the 
manuscript or abstract for review by the Sponsor, and, if necessary, delay publication or communication for 
a limited time in order to protect the confidentiality or proprietary nature of any information contained 
therein. The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
 
 


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15. REFERENCES LIST 
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2. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. 
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3. Edmison J, McCullough AJ. Pathogenesis of nonalcoholic steatohepatitis: human data. Clin 
Liver Dis. 2007;11:75-104. 
4. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 
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5. Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic 
responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34: 
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6. Poniachik J, Santiban˜ez C, Haim D, et al. Enhancement in liver nuclear factor-KB (NF-KB) and 
activator protein 1 (AP-1) DNA binding in obese patients with nonalcoholic fatty liver disease. 
The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 
2008. 
7. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and 
fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288-95. 
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8. Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin 
concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin 
Endocrinol (Oxf). 2006;64:679-683. 
9. Xu H, Barnes G, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the 
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Gastroenterol Hepatol. 2004;16:1095-1105. 
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TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 
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12. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis 
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13. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21-29. 
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nonalcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23(6):1464-1467. 
15. Shan W, Nicol CJ, Bility MT, et al.,Peroxisome proliferator-activated receptor-beta/delta 
protects against chemically induced liver toxicity in mice, Hepatology. 2008;47(1):225-235. 
16. Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated 
receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative 


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stress, 
and 
increases 
fatty 
acid 
oxidation 
in 
moderately 
obese 
men. 
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delta regultate macrophage polarization and insulin sensitivity. Cell. Metab. 2008;7:485-495. 
18. Odegaard JI, Ricardo-Gonzalex RR, Red Eagle A et al. Alternative M2 activation of Kupffer cells 
by PPARδ ameliorates obesity induced insulin resistance. Cell. Metab. 2008;7:496-507. 
19. Cattley RC, Deluca j, Elcombe C, et al. Do peroxisome proliferating compounds pose a 
hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol. 2008;27(1 Pt 1):47-60. 
20. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of nonalcoholic 
fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease 
severity. Ann Med. 2011;43(8):617-649. 
21. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology. 2006;44(4):865-873. 
22. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is 
Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2015;149(2):389-397 e310. 
23. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis 
progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51(2):371-379. 
24. Pagadala MR, McCullough AJ. The relevance of liver histology to predicting  clinically 
meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis 2012;16(3):487-504. 
25. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in 
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of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654. 
26. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and progression of NASH. J 
Gastroenterol. 2011;46(supplement 1):63-69. 
27. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: 
interprotocol 
agreement 
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predict 
liver-related 
mortality. 
Hepatology. 
2011;53(6):1874-1882. 
28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose 
ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011-1019. 
29. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic 
steatohepatitis. Hepatology. 2011;54:344-353. 
30. Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and 
biomarker development for nonalcoholic steatohepatitis: findings and recommendations. 
Hepatology. 2015;61(4):1392-1405. 
31. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to 
fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical 
management. J Hepatol. 2015;62(5):1148-1155. 


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32. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk 
in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263-2271. 
33. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin 
Gastroenterol Hepatol. 2009;7(2):234-328. 
34. Clinical Trial Facilitation Group (2014). Recommendations related to contraception and 
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http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
35. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-965. 
.  
 


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Appendices 


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APPENDIX I – WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
Alcohol type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units 2 
grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor 1 
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
1. 
e.g., gin, rum, vodka, whiskey. 
2. 
Units calculated using the cleave Books calculator for units of drink, using the US definition of 1 unit of 
alcohol as 17.7 mL (14.0 g) of pure alcohol (http://www.cleavebooks.co.uk/scol/ccalcoh3.htm). 


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APPENDIX V: PRODUCT CARTON AND WALLET LABELING 
 
Carton 
Wallet 
Protocol number 
X 
X 
Sponsor details 
X 
X 
Site number 
X 
X 
Subject ID 
X 
X 
Kit number 
X 
X 
Visit number 
X 
- 
Lot number 
X 
X 
Expiry date 
X 
X 
Contents 
X 
X 
Route of administration 
X 
X 
Administration 
instructions 
X 
X 
“For Clinical Trial Use 
only.” 
X 
X 
“Keep out of reach of 
Children.” 
X 
X 
Storage details 
X 
X 
Instructions for product 
and package return at 
next visit 
X 
X