Conditions: Primary Biliary Cholangitis (PBC)
Keywords: Elafibranor Primary Biliary Cholangitis Alkaline phosphatase
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
The primary objective of the study is to compare the effect of daily oral administration of elafibranor 80mg and 120 mg on change in serum alkaline phosphatase (ALP) to that of placebo in patients with PBC and inadequate response to Ursodeoxycholic acid (UDCA).

Detailed description:

Arms:
arm 1: Study subjects will take two tablets per day orally before breakfast with a glass of water each morning arm 2: Study subjects will take two tablets per day orally before breakfast with a glass of water each morning arm 3: Study subjects will take two tablets per day orally before breakfast with a glass of water each morning

Interventions: intervention 1: Elafibranor 80 mg intervention 2: Elafibranor 120 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Two coated tablets daily for 12 weeks intervention 2: Two coated tablets daily for 12 weeks intervention 3: Two coated tablets daily for 12 weeks

Protocol document:
Prot_000.pdf: 
Clinical Trial GFT505B-216-1 
Protocol V3.0 04 December 2017 
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CONFIDENTIAL 
Page 1 of 92 
TITLE PAGE 
CLINICAL PROTOCOL – PHASE 2 
Protocol N° GFT505B-216-1 
EudraCT N°2016-003817-80 
IND number: 132202 
Final 3.0 – Release date 04 December 2017 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the 
Efficacy and Safety of Elafibranor at doses of 80 mg and 120mg After 12 Weeks of Treatment in 
Patients With Primary Biliary Cholangitis and Inadequate Response to Ursodeoxycholic Acid 
International 
Coordinator  
, MD 
Sponsor 
GENFIT 
Parc Eurasanté 
885, Avenue Eugène Avinée 
59120 LOOS, France 
Represented by: 
, MD 
CONFIDENTIAL - This document is the property of the Sponsor and may not - in full or part - be 
passed on, reproduced, published or used by authorities or other applicants for approval or 
registration purposes without express permission of the Sponsor. 
NCT03124108


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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
 
Protocol N°:  
GFT505B-216-1 / EudraCT N° 2016-003817-80/ IND n° 132202 
Version number: 
3.0Release date: 
 
04 December2017 
TITLE: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Evaluate the Efficacy and Safety of Elafibranor at Doses of 80mg 
and 120mg After 12 Weeks of Treatment in Patients With Primary Biliary 
Cholangitis and Inadequate Response to Ursodeoxycholic Acid. 
In signing below, I give agreement to the protocol. 
 
International Coordinator: 
, MD 
 
_______________________________________ 
 
 
 
________________________ 
Signature 
Date (dd-mmm-yyyy) 
 
 


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CLINICAL STUDY PROTOCOL SIGNATURE PAGE 
 
Protocol N°:  
GFT505B-216-1 / EudraCT N° / IND n° 132202 
Version number: 
3.0 
Release date:  
04 December 2017 
TITLE: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Evaluate the Efficacy and Safety of Elafibranor at Doses of 80mg 
and 120mg After 12 Weeks of Treatment in Patients With Primary Biliary 
Cholangitis and Inadequate Response to Ursodeoxycholic Acid. 
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: 
, MD 
 
_______________________________________ 
 
 
________________________ 
Signature 
Date (dd-mmm-yyyy) 
 
 
 


Clinical Trial GFT505B-216-1 
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Page 4 of 92 
CLINICAL STUDY PROTOCOL 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Phase 2 Study to Evaluate the Efficacy and Safety of Elafibranor at   
Doses of 80mg and 120mg After 12 Weeks of Treatment in Patients 
With Primary Biliary Cholangitis and Inadequate Response to 
Ursodeoxycholic Acid. 
PROTOCOL NUMBER: 
 GFT505B-216-1 
EudraCT Number:  2016-003817-80 
IND Number: 132202 
 
CLINICAL PHASE: 
2 
VERSION: 
3.0 
DATE: 
04 December 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°:  
GFT505B-216-1/ EudraCT N° 2016-003817-80/ IND n° 132202 
 
International 
Coordinator  
 
 
 
 
 
 
, MD 
 
 
 
 
 
 
 
 
 
  
 
 
Sponsor 
 
  
GENFIT 
 
Parc Eurasanté 
885, avenue Eugène Avinée 
59120 LOOS - France 
 
 
 
 
CRO for 
monitoring, data 
management & 
statistics 
 
 
 
 
 
 
 
 
 
Project Director 
  
 
 
 
 
Pharmacovigilance 
 
 
 
 
 
 
 
 
 
IXRS  
 
 
 
 
 
 
 
 
 
 
Study drug supplier 
 
 
 
 
 
 
 
  
 
 
 
 


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Central laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CLINICAL TRIAL SYNOPSIS 
Sponsor: 
GENFIT  
Study Drug: 
Elafibranor 
Protocol Number: 
GFT505B-216-1 
Title of the study: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and Safety of 
Elafibranor at Doses of 80 mg and 120mg after 12 Weeks of Treatment in Patients With Primary Biliary Cholangitis 
(PBC) and Inadequate Response to Ursodeoxycholic Acid.  
Phase: 
Phase 2 proof of concept study 
Indication: 
Primary biliary cholangitis 
Study Design and dose levels : 
This is a Phase II, double-blind, randomized, parallel group, placebo-controlled study, evaluating the efficacy and 
safety of elafibranor 80 mg and 120mg once daily (QD) versus placebo in an adult PBC population. 
The study will include a screening visit, followed by a 12 week double-blind treatment period, and a follow-up period 
of at least 16 days but not more than 30 days  after Visit 5. Patients will attend study visits at randomization, Week 2, 
4, 8, and 12 during the treatment period.  
Elafibranor and/or placebo is administered per os, once daily at 80 mg or 120mg, for 12 weeks. 
Route of Administration: 
Oral 
Primary Objectives: 
To evaluate the efficacy of elafibranor 80 and 120 mg with respect to relative change from baseline in serum ALP 
levels compared to placebo. 
Secondary Objectives: 
To assess the following end-points at week 12 
• 
the response to treatment based on composite endpoints: 
o 
ALP < 1.67 × upper limit of normal (ULN) and total bilirubin within normal limit and > 15% 
decrease in ALP 
o 
ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease in ALP 
• 
response according to Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score 
• 
ALP response rates of 10%, 20% and 40% decrease 
• 
response based on the percent of patients who normalized ALP 
• 
response based on the percent of patients who normalized bilirubin  
• 
response based on the percent of patients who normalized albumin  
• 
the change from baseline in ALT, AST, GGT, 5’nucleotidase, total bilirubin, conjugated bilirubin and  
albumin 
• 
the change from baseline in lipid parameters 
• 
the change from baseline in bile acids :  
• 
the change from baseline in C4, FGF19 
• 
the change from baseline in IgM 
• 
The change from baseline in inflammatory and liver fibrosis markers 
• 
the change from baseline in: 
o 
5D-itch scale 
o 
PBC 40 QOL 
o 
VAS 
• 
the tolerability and safety of elafibranor 80 and 120 mg in patients with PBC 
 
Exploratory Objective: 
• 
Determine the pharmacokinetics (PK) parameters of elafibranor (GFT505) 80 and 120 mg and its main active 
circulating metabolite, GFT1007, in patients with PBC and to explore an exposure-response relationship  
 


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Study Population: 
Subjects with PBC, with inadequate response to UDCA  
Number of Patients (planned): 45 patients (15 per treatment group) 
Number of Sites (planned):~20 clinical units 
Country (planned): US, UK, Spain, Germany 
Study duration per patient:  
A screening period (1 to 4 weeks before randomization) will precede a 12-week double-blind treatment period, after 
which there will be a follow-up period of up to 30 days.  
Schedule: 
• Screening visit: Week-4 to Week-1 prior to randomization 
• Week 0 to Week 12: period of treatment with elafibranor (GFT505) 80mg or 120 mg or placebo for 12 weeks. 
Patients will attend study visits at randomization, Week 2, 4, 8, and 12. 
• Week 12 to Week 16: patients who complete the 12 week double blind treatment period will have a follow up 
period and attend  an End of Study visit at least 16 days but no more than 30 days after Visit 5 (V5) 
Inclusion Criteria: 
1. Must have provided written informed consent (IC) 
2. Males or females 18 to 75 years of age 
3. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the following 3 
diagnostic factors: 
o 
History of elevated ALP levels for at least 6 months Positive Anti-Mitochondrial Antibodies (AMA) 
titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay 
[ELISA]) or positive PBC-specific antinuclear antibodies  
o 
Liver biopsy consistent with PBC 
4. ALP ≥ 1.67x upper limit of normal (ULN) (‘inadequate response to UDCA’)   
5. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit  
6. Contraception: Females participating in this study must be of non-childbearing potential or must be using 
highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as 
described below: 
a) Cessation of menses for at least 12 months due to ovarian failure 
b) Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian 
failure 
c) Using a highly effective non-hormonal method of contraception (bilateral tubal occlusion, vasectomised 
partner or intra-uterine device) 
d) 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. 
7. Must agree to comply with the trial protocol. 
Exclusion criteria: 
1. History or presence of other concomitant liver diseases including: 
• 
Positive hepatitis B surface antigen (HBsAg) at Screening 
• 
Positive HCV RNA (tested for in case of known cured HCV infection, or positive HCV Ab at screening) 
• 
Alcoholic liver disease 
• 
Primary sclerosing cholangitis (PSC) 
• 
Definite autoimmune hepatitis (AIH), or ‘AIH-PBC overlap syndrome’; the existence of AIH is defined 
as continuing use of budesonide or other systemic corticosteroid therapy, and/or azathioprine, and/or 
other immunosuppressive therapy following an historical AIH diagnosis (EASL 2015). ‘AIH-PBC 
overlap syndrome’ is based upon fulfilment of the ‘Paris criteria’ (Chazouillères 1998) for both AIH 
(ALT ≥5x ULN; IgG ≥2x ULN or smooth muscle antibody; interface hepatitis), and PBC(ALP ≥2x 
ULN; AMA, and non-suppurative bile duct injury/destruction), requiring corticosteroid therapy for 


Clinical Trial GFT505B-216-1 
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disease management, either currently or in the past. 
• 
Biopsy confirmed Nonalcoholic Steatohepatitis (NASH) 
• 
Known history of alpha-1 antitrypsin deficiency, or other metabolic forms of chronic liver disease 
• 
Gilbert's Syndrome (due to interpretability of bilirubin levels) 
2. Screening CPK > ULN 
3. Screening ALT or AST > 5 ULN 
4. Screening total bilirubin > 2 ULN 
5. Screening serum creatinine > 1.5 mg/dl and eGFR < 60 mL/min/1.73 m2, at screening 
6. Significant renal disease, including nephritic syndrome, chronic kidney disease  
7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh class B, C) 
8. Platelet count <150 X 10 3/microliter 
9. Albumin <3.5 g/dL 
10. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: 
• 
Current Model for End Stage Liver Disease (MELD) score ≥ 15; current placement on a liver transplant 
list, or history of undergoing liver transplantation 
• 
Any record of complications of cirrhosis and/or portal hypertension such as: 
o 
Gastroesophageal variceal bleeding and endoscopic therapy and/or transjugular intrahepatic 
portosystemic shunt [TIPS] insertion 
o 
Ascites formation requiring intervention, e.g. diuretic therapy 
o 
Spontaneous bacterial peritonitis 
o 
Hepatic encephalopathy  
o 
Confirmed or suspected hepatocellular carcinoma 
11. Hepatorenal syndrome (type I or II) Administration of the following medications is prohibited as specified 
below: 
• 
From pre-randomization to EOT or V5 visit : indomethacin 
• 
2 months preceding screening and throughout the trial (up to the last study visit): fibrates or obeticholic 
acid, thiazoledinediones, glitazones 
• 
3 months prior to screening and throughout the trial (up to the last study visit): azathioprine, colchicine, 
cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; budesonide and other chronic 
systemic corticosteroids; and potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic 
acid, isoniazide, or nitrofurantoin) 
• 
12 months prior to inclusion visit and throughout the trial (up to the last study visit): antibodies or 
immunotherapy directed against interleukins or other cytokines or chemokines 
• 
NOTE : Anti-pruritus treatment, including rifamycin, is allowed if prescribed for at least 6 months prior 
to screening, and on stable dose at least 3 months prior to screening. and continues at the same dose 
throughout the study 
12. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy 
test), or lactating 
13. Known history of human immunodeficiency virus (HIV) infection 
14. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)  
15. Other clinically significant medical conditions that are not well controlled or for which medication needs are 
anticipated to change during the trial 
16. Anticipated changes to current medications (that will be continued) during the course of the trial 
17. History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day for men, and more 
than 20 g pure alcohol per day for women, or other substance abuse within 1 year prior to Day 0 
(randomization visit) 
18. Participation in another trial with an investigational drug, biologic, or medical device using active substance 
within 30 days prior to screening, or within 5 half lives of the active substance, whichever is longer. 
19. History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable 
20. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is 
uncertain 


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21. Known hypersensitivity to the investigational product or any of its formulation excipients 
22. Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematological, 
gastrointestinal, neurological, neoplastic, or psychiatric disease. 
Randomization:  
Patients who satisfy all eligibility criteria will be randomized in a 1:1:1 ratio to one of the following groups: 
− 
Elafibranor 80 mg 
− 
Elafibranor 120 mg 
− 
Placebo  
A central randomization system will be used (interactive voice/web response system [IVRS/IWRS]). 
Criteria for Evaluation: 
Primary Endpoint: 
Relative change in serum ALP from baseline to end of treatment in each elafibranor arm, compared to placebo 
Secondary Endpoints:  
The secondary endpoints are to assess at Week 12: 
• 
Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less 
than 1.67 times ULN and total bilirubin within normal limits and ALP reduction > 15%.  
• 
Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less 
than 2  times ULN and total bilirubin within normal limits and ALP reduction > 40%  
• 
Response rate according to Paris I, Paris II, Toronto I, Toronto II, UK PBC risk score  
• 
Alkaline phosphatase response rates of 10%, 20% and 40% decrease 
• 
Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent 
of patients with normalized  ALP at the end of treatment 
• 
Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent 
of patients with normalized bilirubin at the end of treatment 
• 
Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent 
of patients with normalized albumin at the end of treatment 
• 
Changes from baseline in:  
o 
Gamma-glutamyl transferase (GGT)  
o 
Alanine aminotransferase (ALT)  
o 
Aspartate aminotransferase (AST)  
o 
5’nucleotidase 
o 
Bilirubin (total and conjugated)  
o 
Albumin  
o 
total cholesterol, LDL-chol, HDL-Chol, Triglycerides 
o 
Bile acids :  
o 
C4, FG19 
o 
IgM  
o 
Quality of Life: PBC 40 QOL 
o 
Pruritus: 5-D Pruritus Questionnaire and Visual Analogue Score (VAS) 
o 
Biomarkers of inflammation and liver fibrosis: TNF-α, TGF-β, IL-6, CK-18 and 
lysophosphatidic acid 
• 
Adverse Events (AEs)  
• 
Cardiovascular parameters (12-lead ECG, heart rate, blood pressure) 
• 
Hematology and safety parameters  
• 
Liver Markers 
• 
Other biochemical safety markers 
Exploratory Endpoint:  
Determine PK parameters of elafibranor (GFT505) and its metabolite GFT1007 at two daily doses 80 mg and 120 mg 
in patients with PBC and explore an exposure-response relationship. 


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Study Duration (planned): estimated 14 months (First Patient First Visit [FPFV]-Last patient last visit [LPLV]) 
• 
Regulatory/ethics committee submission: September 2016- December 2016 
• 
Initiation visits: January 2017 – March 2017 
• 
Recruitment period: March 2017 – December 2017 
• 
FPFV: March 2017 
• 
LPLV: April 2018 
 
 


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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 INVESTIGATOR SIGNATURE PAGE ................................................................. 4 
STUDY CONTACTS ...................................................................................................................................................... 5 
CLINICAL TRIAL SYNOPSIS ...................................................................................................................................... 7 
TABLE OF CONTENTS............................................................................................................................................... 12 
LIST OF TABLES ......................................................................................................................................................... 17 
LIST OF FIGURES ....................................................................................................................................................... 17 
LIST OF ABBREVIATIONS ........................................................................................................................................ 18 
1. 
INTRODUCTION AND RATIONALE ....................................................................................................... 21 
1.1. 
BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY 
CHOLANGITIS ............................................................................................................................................ 21 
1.2. 
SUMMARY OF NONCLINICAL STUDIES .............................................................................................. 23 
1.2.1. 
Safety Pharmacology ....................................................................................................................... 23 
1.2.2. 
Absorption/Distribution/Metabolism/Excretion Studies (ADME) .................................................. 23 
1.2.3. 
Toxicology ....................................................................................................................................... 24 
1.2.3.1. 
Mutagenicity and Genotoxicity ....................................................................................................... 24 
1.2.3.2. 
Acute Toxicity ................................................................................................................................. 24 
1.2.3.3. 
Repeated Dose Toxicity Studies ...................................................................................................... 24 
1.2.3.4. 
Phototoxicity Studies ....................................................................................................................... 25 
1.3. 
CLINICAL STUDIES .................................................................................................................................. 25 
1.3.1. 
Phase I Program ............................................................................................................................... 25 
1.3.2. 
Phase II Program.............................................................................................................................. 26 
1.4. 
CONCLUSION ............................................................................................................................................. 28 
2. 
TRIAL OBJECTIVES .................................................................................................................................. 29 
2.1. 
PRIMARY OBJECTIVES ............................................................................................................................ 29 
2.2. 
SECONDARY OBJECTIVES ...................................................................................................................... 29 
2.3. 
EXPLORATORY OBJECTIVE ................................................................................................................... 29 
2.4. 
SAFETY SECONDARY OBJECTIVES ...................................................................................................... 29 
3. 
TRIAL DESIGN ........................................................................................................................................... 30 
3.1. 
NUMBER OF PATIENTS ........................................................................................................................... 30 
3.2. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .......................................................... 30 
3.3. 
DOSE ADJUSTMENT CRITERIA .............................................................................................................. 30 
3.4. 
DURATION OF STUDY PARTICIPATION .............................................................................................. 30 
3.5. 
STUDY PERIODS AND SCHEDULE OF ASSESSMENTS ...................................................................... 32 
3.5.1. 
Screening Period .............................................................................................................................. 32 
3.5.1.1. 
Screening Visit [SV] (Week -4 to Week -1) .................................................................................... 32 


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3.5.1.2. 
Pre-Randomization Visit [PRV] (Week -1) ..................................................................................... 33 
3.5.2. 
Treatment Period (Week 0 to Week 12) .......................................................................................... 33 
3.5.2.1. 
Randomization Visit V1 (Week 0) .................................................................................................. 33 
3.5.2.2. 
Treatment Period Visits V2 to V5 (Week 2 to Week 12) ................................................................ 34 
3.5.3. 
End of Treatment Visit [EOT] ......................................................................................................... 34 
3.5.4. 
End of Study Visit [EOS] ................................................................................................................ 35 
3.5.5. 
Optional Visits ................................................................................................................................. 35 
3.5.5.1. 
Retesting Screening Visits ............................................................................................................... 35 
3.5.5.2. 
Unscheduled Visits .......................................................................................................................... 35 
4. 
PATIENT SELECTION ............................................................................................................................... 39 
4.1. 
INCLUSION CRITERIA .............................................................................................................................. 39 
4.2. 
EXCLUSION CRITERIA ............................................................................................................................ 39 
5. 
TRIAL PROCEDURES ................................................................................................................................ 42 
5.1. 
STUDY RECOMMENDATIONS ................................................................................................................ 42 
5.1.1. 
Dietary, Fluid, and Lifestyle Restrictions ........................................................................................ 42 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES .................. 43 
5.2.1. 
Handling of Patient Withdrawal ...................................................................................................... 43 
5.2.2. 
Permanent Discontinuations of Study Drug..................................................................................... 43 
5.2.3. 
Patient Discontinuation From the Study .......................................................................................... 43 
5.2.4. 
Patients Lost to Follow-Up .............................................................................................................. 44 
5.2.5. 
Replacement .................................................................................................................................... 44 
5.2.6. 
Premature Discontinuation of the Study .......................................................................................... 44 
5.3. 
PATIENT RESCREENING ......................................................................................................................... 44 
6. 
ASSESSMENTS ........................................................................................................................................... 45 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS ............................................................................................. 45 
6.1.1. 
Biological Assessments ................................................................................................................... 45 
6.1.1.1. 
Laboratory Assessments .................................................................................................................. 45 
6.1.1.2. 
Urinary Pregnancy Tests .................................................................................................................. 45 
6.1.1.3. 
Serology (SB1) ................................................................................................................................ 45 
6.1.1.4. 
Other Parameters ............................................................................................................................. 46 
6.1.2. 
Pharmacokinetics Evaluation ........................................................................................................... 46 
6.1.2.1. 
Description of Pharmacokinetic Evaluation Parameters .................................................................. 46 
6.1.2.2. 
Pharmacokinetic Analysis................................................................................................................ 46 
6.1.2.3. 
Pharmacokinetic Blood Sampling Timepoints ................................................................................ 46 
6.1.2.4. 
Pharmacokinetic Blood Handling Procedures ................................................................................. 46 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING ..................................... 47 
6.2.1. 
Physical Examination ...................................................................................................................... 47 
6.2.2. 
Vital Signs ....................................................................................................................................... 47 
6.2.3. 
Electrocardiogram ............................................................................................................................ 47 
6.2.4. 
Patient Reported Outcomes Questionnaires ..................................................................................... 47 


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6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT 
DISCONTINUATION RULES .................................................................................................................... 47 
6.3.1. 
Creatine Phosphokinase ................................................................................................................... 47 
6.3.2. 
Liver Function Monitoring .............................................................................................................. 48 
6.3.2.1. 
Monitoring of Patients With Normal Baseline Aminotransferase Values ....................................... 48 
6.3.2.2. 
Monitoring of Patients With Increased Baseline AT Values ........................................................... 48 
6.3.3. 
Specific Biological Monitoring ....................................................................................................... 49 
6.3.4. 
Safety and Efficacy Data Review .................................................................................................... 49 
6.3.5. 
Guidance for Investigators ............................................................................................................... 49 
7. 
TREATMENTS ............................................................................................................................................ 53 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ............................................................................................ 53 
7.2. 
PACKAGING AND LABELING ................................................................................................................ 53 
7.2.1. 
Packaging ......................................................................................................................................... 53 
7.2.2. 
Labeling ........................................................................................................................................... 53 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO .......................................... 53 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .......................................................... 54 
7.5. 
STORAGE CONDITIONS ........................................................................................................................... 54 
7.6. 
DISPENSING OF TREATMENT ................................................................................................................ 54 
7.7. 
TREATMENT REPLACEMENT ................................................................................................................ 54 
7.8. 
PROCEDURE FOR BLINDING .................................................................................................................. 55 
7.9. 
PROCEDURE FOR UNBLINDING ............................................................................................................ 55 
7.10. STUDY DRUG COMPLIANCE .................................................................................................................. 55 
7.11. TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION. ........................................... 55 
7.12. OTHER MEDICATION ............................................................................................................................... 56 
7.12.1. 
Handling of Concomitant Medication ............................................................................................. 56 
7.12.2. 
Non-Permitted Medication .............................................................................................................. 56 
7.12.3. 
Permitted Medication Under Conditions ......................................................................................... 56 
7.12.4. 
Permitted Medication ....................................................................................................................... 57 
8. 
ADVERSE EVENT AND TOXICITY MANAGEMENT ........................................................................... 58 
8.1. 
DEFINITIONS.............................................................................................................................................. 58 
8.1.1. 
Adverse Events ................................................................................................................................ 58 
8.1.2. 
Serious Adverse Events ................................................................................................................... 59 
8.1.2.1. 
Life-Threatening Adverse Events .................................................................................................... 59 
8.1.2.2. 
Inpatient or Prolonged Hospitalization ............................................................................................ 59 
8.1.2.3. 
Significant or Incapacitating Disability ........................................................................................... 59 
8.1.2.4. 
Medically Important Conditions ...................................................................................................... 60 
8.1.3. 
Clarification on Serious Adverse Events ......................................................................................... 60 
8.1.4. 
Adverse Drug Reaction .................................................................................................................... 60 
8.1.5. 
Unexpected Adverse Event .............................................................................................................. 60 
8.2. 
ASSESSMENTS ........................................................................................................................................... 61 
8.2.1. 
Intensity Assessment ....................................................................................................................... 61 


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8.2.2. 
Relation to the Study Treatment ...................................................................................................... 61 
8.2.3. 
Action Taken and Outcome ............................................................................................................. 61 
8.3. 
REPORTING ................................................................................................................................................ 62 
8.3.1. 
Reporting an Adverse Event ............................................................................................................ 62 
8.3.2. 
Reporting a Serious Adverse Event ................................................................................................. 62 
8.3.3. 
Follow-Up ........................................................................................................................................ 64 
8.4. 
POST STUDY REPORTING REQUIREMENTS ....................................................................................... 64 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS 
ADVERSE EVENTS OR SERIOUS ADVERSE EVENTS ........................................................................ 64 
8.6. 
SPECIAL SITUATION REPORTS .............................................................................................................. 64 
8.6.1. 
Pregnancy ........................................................................................................................................ 64 
8.6.2. 
Medication Error .............................................................................................................................. 65 
8.6.3. 
Misuse .............................................................................................................................................. 65 
8.6.4. 
Overdose .......................................................................................................................................... 65 
8.6.5. 
Abuse ............................................................................................................................................... 65 
9. 
STATISTICAL METHODS AND DATA ANALYSIS ............................................................................... 66 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT ....................................................................... 66 
9.2. 
ENDPOINTS ................................................................................................................................................ 66 
9.2.1. 
Primary Endpoint ............................................................................................................................. 66 
9.2.2. 
Secondary Endpoints ....................................................................................................................... 66 
9.2.3. 
Exploratory Endpoint ....................................................................................................................... 67 
9.3. 
ANALYSIS SETS ........................................................................................................................................ 67 
9.4. 
ANALYSIS OF PRIMARY ENDPOINT ..................................................................................................... 67 
9.4.1. 
Reduction in Serum Alkaline Phosphatase ...................................................................................... 67 
9.5. 
OTHER STATISTICAL ANALYSIS .......................................................................................................... 68 
9.5.1. 
Secondary Endpoints ....................................................................................................................... 68 
9.6. 
STRATEGIES TO CONTROL TYPE I ERROR ......................................................................................... 68 
9.7. 
SAMPLE SIZE CALCULATION ................................................................................................................ 68 
9.7.1. 
Reduction in ALP ............................................................................................................................ 68 
9.8. 
PHARMACOKINETIC ANALYSIS ........................................................................................................... 69 
9.9. 
SAFETY ANALYSIS ................................................................................................................................... 69 
10. 
DATA HANDLING AND RECORD KEEPING ......................................................................................... 70 
10.1. CASE REPORT FORM AND SOURCE DOCUMENTS ............................................................................ 70 
10.2. RETENTION OF RECORDS ....................................................................................................................... 70 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................ 72 
11.1. QUALITY CONTROL & MONITORING PROCEDURES ....................................................................... 72 
11.2. ETHICAL PRINCIPLES .............................................................................................................................. 72 
11.3. QUALITY ASSURANCE ............................................................................................................................ 72 
12. 
ETHICS AND REGULATORY ................................................................................................................... 74 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ..................................... 74 
12.2. COMPETENT AUTHORITY ...................................................................................................................... 74 


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12.3. PATIENT INFORMATION AND CONSENT ............................................................................................ 74 
12.4. PATIENT CONFIDENTIALITY ................................................................................................................. 75 
12.5. DEFINITION OF THE END OF THE RESEARCH ................................................................................... 75 
13. 
FINANCING AND INSURANCE ............................................................................................................... 76 
13.1. FINANCIAL ISSUES ................................................................................................................................... 76 
13.2. INSURANCE AND PATIENT INJURY ..................................................................................................... 76 
14. 
STUDY RESULTS AND PUBLICATION POLICY .................................................................................. 77 
14.1. STUDY REPORT ......................................................................................................................................... 77 
14.2. CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND 
PUBLICATION ............................................................................................................................................ 77 
15. 
REFERENCES LIST .................................................................................................................................... 79 
APPENDICES ............................................................................................................................................................... 81 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ........................................... 81 
APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION ........................................................................... 90 
APPENDIX IV: ALCOHOL COMPARISON TABLE ................................................................................................ 91 
APPENDIX V: PRODUCT CARTON AND WALLET LABELING .......................................................................... 92 
 
 


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List of Tables 
Table 1: Study General Assessment Schedule ............................................................................................................... 37 
Table 2: Study Biological Assessment Schedule ........................................................................................................... 38 
Table 4: Non-Permitted Medication and Condition ....................................................................................................... 90 
Table 5: Permitted Medication and Condition ............................................................................................................... 90 
 
 
 
List of Figures 
Figure 1: Overview of Study Design ............................................................................................................................. 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 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATP 
Adult Treatment Panel 
BCL6 
B-cell lymphoma 6 
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 
CK-18 
cytokeratin-18 
CPK 
creatine phosphokinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
C4 
Serum 7α-hydroxy-4-cholesten-3-one 
DCA 
deoxycholic acid 
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 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of study treatment 
FDA 
Food and Drug Administration 
FGF19 
Fibroblast Growth Factor 19 
FITT 
full intent-to-treat set 
FPFV 
first patient first visit 
FSS 
full safety set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma  


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HCV 
hepatitis C Virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
hPPAR 
human peroxisome proliferator-activated receptor 
HRT 
Hormonal replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL-6 
interleukin-6 
IgM 
immunoglobulin M 
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 
LSS 
Life Science Services 
M2 
anti-inflammatory macrophages 
MA 
Marketing Authorisation 
MAA  
Marketing Authorisation Application 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for end-stage liver disease 
MDRD 
Modification of diet in renal disease 
NASH 
nonalcoholic steatohepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
NF-κB 
Nuclear factor kappa B 
NICE 
National Institute for Health and Care Excellence  
PBC 
Primary Biliary Cholangitis 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PKS 
Pharmacokinetic set 
PPAR 
peroxisome proliferator-activated receptor 
PPS 
per protocol set 
PRV 
Pre-randomization visit 
PT 
prothrombin time 
QD 
once daily 
QoL 
quality of life 
QTc 
corrected QT 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBx 
screening biological assessment visit 
SOP 
Standard Operating Procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 


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SV 
Screening Visit  
TGF-β 
transforming growth factor beta 
 
 
TNFα 
Tumor Necrosis Factor-alpha 
UDCA 
Ursodeoxycholic Acid 
UK 
United Kingdom 
ULN 
upper limit of normal 
UV-LLNA 
UV- Local Lymph Node Assay 
VAS 
Visual Analogue Score 
Vx 
Visit x 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION AND RATIONALE 
1.1. 
BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY CHOLANGITIS 
Characterization of the Disease  
Primary Biliary Cholangitis (PBC) is a rare, chronic, progressive liver disease of autoimmune 
etiology, characterized by injury of the intrahepatic bile ducts that, in untreated patients or non-
responders to existing therapies, may progress to hepatic fibrosis, cirrhosis, hepatic 
decompensation, and death unless they receive a liver transplant (Kuiper 2010; Kumagi 2008). 
PBC disproportionately affects women versus men (approximately 10:1) and is typically 
diagnosed in patients between 40 years to 60 years of age. The incidence and prevalence rates for 
PBC in Europe, North America, Asia, and Australia are reported as ranging from 0.33 to 5.8 per 
100,000 inhabitants and 1.91 to 40.2 per 100,000 inhabitants, respectively (Boonstra 2012). Kim 
et al estimated that there were 47,000 prevalent cases of PBC in the United States white 
population and that approximately 3500 new cases are diagnosed each year (Kim 2000). Over 
60% of the newly diagnosed cases are asymptomatic. The majority of asymptomatic patients 
become symptomatic within 10 years and the estimates for developing symptoms at 5 and 20 
years are 50% and 95%, respectively (Kumagi 2008). Patients with PBC progress at varying rates, 
some having liver decompensation over a period of several years while for others progression 
occurs over more than a decade (Al-Harthy 2012; Selmi 2011). PBC is one of the leading 
indications for liver transplantation. Despite its rarity, PBC remains therefore an important cause 
of morbidity in the Western world.  PBC has also been identified as an important risk factor for 
hepatocellular carcinoma (Ali 2015). 
PBC is characterized by cholestasis caused by autoimmune destruction of biliary ductules with 
progressive impairment of bile flow in the liver. This results in increased hepatocellular bile acid 
concentrations which are toxic to the liver. Such hepatocellular injury is associated with a local 
inflammatory response resulting early on in an abnormal elevation of serum alkaline phosphatase 
(ALP) levels, a hallmark of the disease.  Antimitochondial antibody and immunoglobulin M are 
specific immunological hallmarks of PBC, and antimitochondial antibody is a diagnostic marker 
of the disease in approximately 90% of patients (Hirschfield 2013). Liver biopsy, while 
confirmatory, is no longer the standard of care.  
ALP is also routinely used to clinically monitor the disease and serves as a leading indicator of 
disease progression. ALP increases with disease progression as bilirubin starts to decline in more 
advanced disease (as the excretory function starts to decline), and both have been shown to be 
highly predictive of long-term clinical outcomes, e.g., transplant-free survival (Beuers 2011; 
Lammers 2014; Carbone 2013). Two large clinical PBC databases, the PBC Study Group 
(>6100 patients) and the UK-PBC Research Cohort (>5900 patients) have confirmed a near log-
linear correlation of both elevated ALP and bilirubin after 1 year of follow up with long-term liver 
transplant-free survival (Lammers 2014). 
As PBC advances, the transaminases alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) may also be elevated due to hepatocellular damage secondary to 
cholestasis. While gamma-glutamyl transferase (GGT) lacks specificity, elevation of this enzyme 
in the presence of elevated ALP is confirmatory of a cholestatic condition such as PBC 
(Giannini 2005).  
The most common symptoms of PBC are fatigue and pruritus (Crosignani 2008). The mechanisms 
underlying these symptoms are not well elucidated and neither correlates with disease stage or 
clinical outcomes.  


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Current Treatment Options 
Ursodeoxycholic acid (UDCA), an epimer of the primary human bile acid chenodeoxycholic acid, 
was the only medicine currently approved to treat PBC until May 2016. UDCA has been shown to 
improve ALP and bilirubin, and to delay histological progression, thereby increasing liver 
transplant-free survival (Corpechot 2008). Accordingly, UDCA treatment has been recommended 
as first line therapy for patients with PBC in the treatment guidelines of the American Association 
for the Study of Liver Diseases (AASLD: Lindor 2009) and the European Association for the 
Study of the Liver (EASL 2009). While UDCA has had a marked impact on clinical outcomes in 
PBC, a large proportion of patients have an inadequate response. It is estimated (Ali 2015) that up 
to 40% of UDCA-treated patients have a suboptimal response to UDCA.  Lammers and colleagues 
found that ALP remains elevated in up to 70% of patients who are currently being treated or are 
intolerant to UDCA (Lammers 2014). Such patients remain at risk of disease progression and 
longer term adverse clinical outcomes.   
Ocaliva (obeticholic acid, OCA), at doses from 5 to 10 mg, was approved as a second line therapy 
by the Food and Drug Administration (FDA) in May 2016 under the accelerated approval 
regulations based on a reduction in ALP, either as a monotherapy in adults unable to tolerate 
UDCA or in combination with UDCA in adults with an inadequate response.  
On 12 December 2016, the European Commission granted a conditional Marketing Authorization 
(MA) valid throughout the European Union for Ocaliva for the same indication. In the UK, the 
National Institute for Health and Care Excellence (NICE) recently approved Ocaliva for use as 
treatment in the UK making it available to patients. Ocaliva is  also approved in Germany, and 
Spain.  
Datafrom the Phase 2a study suggest the potential for exacerbation of pruritis. In a Phase 1 dose 
ranging study, more severe pruritus (although with no higher incidence) was observed in the 10 
mg OCA group than in the placebo arm. This Adverse Event (AE) was shown to be clearly OCA-
dose related (Hirschfield 2015). The incidence of pruritus in the open-label extension study phase 
was 87% (68/78), and 13% (10/78) discontinued OCA due to severe pruritus (Ali 2015).  
At present, despite near universal use of UDCA, 10%, 22% and 44% of UDCA-treated patients 
are progressing to liver transplant or death over 5, 10, and 15 years, respectively (Lammers 2014). 
While research has been conducted on a number of other drugs (eg, malotilate, thalidomide, 
silymarin, atorvastatin, azathioprine, methotrexate, colchicine, D-penicillamine, cyclosporin A, 
chlorambucil and glucocorticosteroids), little to no evidence supports the benefit of these 
compounds (Lindor 2009, Rudic 2012, EASL 2009).  The European Association for the Study of 
the Liver (EASL 2009) mentioned, however, that the PPARα agonist, bezafibrate, deserved 
further studies as well as sulindac and the antiretroviral strategy consisting of a combination of 
lamivudine and zidovudine (Combivir).  
Rationale for Evaluation of Elafibranor in PBC 
Elafibranor is being developed by Genfit for the treatment of PBC, based on its pharmacological 
properties as a PPARα/δ agonist. Activation of PPARα receptors leads to a decrease in bile acid 
synthesis, increase in bile acid uptake, and increased detoxification of bile acids through the 
increased uptake in micelles. PPARα and PPARδ receptor activation also has anti-inflammatory 
effects by acting on different pathways of inflammation (NF-κB and BCL6 pathways).  
Ligand-activated PPARα contributes to a range of actions, including cholesterol and bile acid 
homeostasis. PPARα primarily downregulates bile acid synthesis. PPARα also interferes with pro-
inflammatory transcription factor pathways leading to the hypothesis that fibrates may exert their 
beneficial effect on cholestatic liver function by also regulating anti-inflammatory pathways. 


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Fenofibrate may also ameliorate cholestatic liver disease through its transcriptional activation of 
MDR3 (Ghonem 2015).  
While large-scale multicenter clinical studies are awaited, several pilot studies have consistently 
shown that fibrates might be of therapeutic benefit in patients with cholestatic liver diseases, 
particularly PBC. Use of fibrates results in a significant reduction in cholestatic parameters (serum 
ALP and GGT), transaminases, and immunoglobulin M (IgM) levels in PBC. Effects of fibrates 
on biochemical parameters can be observed as early as one month after the beginning of therapy, 
and most patients sustained the biochemical response as long as they were on fibrates.  
Discontinuation of fibrates results in rebound elevation of biochemical indices in patients with 
PBC, and an improvement in the biochemical indices is almost always observed after treatment 
with fibrates is reinstituted, further supporting the potential therapeutic benefit in PBC (Ali 2015).  
In addition to the biochemical improvement, significant pruritus relief has been observed in 
patients with PBC with inadequate response to UDCA following institution of fibrate therapy 
(Lens 2014). Patients experienced worsening of pruritus when bezafibrate was discontinued, and 
pruritus improved or completely disappeared after bezafibrate was reinstituted. These data lend 
support to the use of fibrates in PBC patients, and suggest that fibrates could be used in the 
management of pruritus.   
1.2. 
SUMMARY OF NONCLINICAL STUDIES 
1.2.1. Safety Pharmacology 
Any potential effects on the cardiovascular, respiratory, and central nervous system have been 
assessed and no safety issue was identified. 
1.2.2. 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). 


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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 its 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%). 
1.2.3. Toxicology 
1.2.3.1. 
Mutagenicity and Genotoxicity 
The toxicology program performed according to the International Council for Harmonisation 
(ICH) guidelines demonstrates that elafibranor has no genotoxic or mutagenicity potential. 
1.2.3.2. 
Acute Toxicity 
According to acute toxicity study 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. 
1.2.3.3. 
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 (Cattley 2008).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 weight gain, hemodilution, edema, cardiomegaly, 
adiponectin induction, or urinary bladder carcinoma. Importantly, the non clinical studies have 
demonstrated a reduced plasma ALP activity in monkeys treated for 3 or 12 months with 
elafibranor 


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1.2.3.4. 
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. 
1.3. 
CLINICAL STUDIES 
1.3.1. 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 mg 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 mg 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 mg to 
240 mg, were also assessed in these 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). 


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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 (ie, 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). 
The last part of the study GFT505-115-12 has been completed. The objective was 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 doses of elafibranor. 
1.3.2. 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 also been completed (, and evaluated 
the efficacy and safety of elafibranor 80 mg and 120 mg on steatohepatitis in 274 patients with 
nonalcoholic steatohepatitis (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 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. 


Clinical Trial GFT505B-216-1 
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CONFIDENTIAL 
Page 27 of 92 
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 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 GGT and ALP were observed and reached up to -29% for GGT 
and -25% for ALP 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 nonalcoholic steatohepatitis (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. 


Clinical Trial GFT505B-216-1 
Protocol V3.0 04 December 2017 
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CONFIDENTIAL 
Page 28 of 92 
The study results 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 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 5 
SAEs reported treated with elafibranor were considered by the sponsor as reasonably related to 
treatment after further analysis. 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). 
1.4. 
CONCLUSION 
In nonclinical studies, plasma ALP activity was reduced in monkeys treated for 3 or 12 months 
with elafibranor.  Moreover, in the Phase 2a and 2b program, elafibranor has consistently shown a 
significant decrease in liver enzymes, notably in ALP. A decrease in ALP levels is recognized as a 
particularly relevant surrogate marker for the treatment of PBC, and was recently used as the basis 
for FDA approval of OCA in this indication.  Elafibranor has also demonstrated significant anti-
inflammatory properties in the phase 2a and 2b program. 
The good safety profile of elafibranor was demonstrated through its development, including the 
therapeutic dose of 120 mg selected for the Phase 3 study in NASH. 
Based on the mechanism of action of elafibranor, and on the relevant efficacy and safety data up  
to the phase 2B study,  specifically the ALP decrease and inflammation markers, Genfit has 
decided to launch a phase 2 study in PBC patients, in order to validate the efficacy of elafibranor 
on ALP decrease, and to confirm its safety in this population. 
Additional information can be found in the Investigator’s Brochure. 


Clinical Trial GFT505B-216-1 
Protocol V3.0 04 December 2017 
GENFIT 
CONFIDENTIAL 
Page 29 of 92 
2. 
TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVES 
To evaluate the efficacy of elafibranor 80 and 120 mg with respect to relative change from 
baseline in serum ALP levels compared to placebo.  
2.2. 
SECONDARY OBJECTIVES 
To assess the following endpoints at Week 12: 
• the response to treatment based on composite endpoints: 
o ALP < 1.67 × upper limit of normal (ULN) and total bilirubin within normal limit 
and > 15% decrease in ALP 
o ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease in ALP 
• response according to Paris I, Paris II, Toronto I, Toronto II, UK PBC risk score 
• ALP response rates of 10%, 20% and 40% decrease the response to treatment on 
normalization of ALP the response to treatment on normalization of bilirubin 
• the response to treatment on normalization of albumin 
• the change from baseline in ALT, AST, GGT, 5’nucleotidase, total bilirubin, conjugated 
bilirubin and albumin 
• the change from baseline in lipid parameters 
• the change from baseline in bile acidsthe change from baseline in C4, FGF19 
• the change from baseline in IgM 
• the change from baseline in inflammatory and liver fibrosis markers 
• the change from baseline in pruritus (through 5D-itch scale and visual analogue score 
VAS) 
• the changes from baseline in Quality of Life (using PBC 40 questionnaire) 
2.3. 
EXPLORATORY OBJECTIVE 
To determine PK parameters of elafibranor (GFT505) 80 and 120mg and its main active 
circulating metabolite, GFT1007, in patients with PBC and to explore an exposure-response 
relationship. 
2.4. 
SAFETY SECONDARY OBJECTIVES 
To assess the tolerability and safety of once a day administration of oral doses of elafibranor at 
80 mg and 120 mg in patients with PBC: 
• Serious adverse events (SAEs), adverse events (AEs), physical examination, vital signs, 
medical history, ECG 
• Hematological parameters 
• Liver markers 
• Other biochemical safety markers 


Clinical Trial GFT505B-216-1 
Protocol V3.0 04 December 2017 
GENFIT 
CONFIDENTIAL 
Page 30 of 92 
3. 
TRIAL DESIGN 
This is a Phase II, double-blind, randomized, parallel group,, placebo-controlled study, evaluating 
the efficacy and safety of elafibranor at doses of 80 mg and 120 mg QD versus placebo in an adult 
PBC population.  
It is planned to randomize patients to either active or placebo treatment in a 1:1:1 ratio.  
The overall study design is presented in Figure 1.  
Patient participation will be 20 weeks maximum (including authorized margins). At the Screening 
Visit (Week -4 to Week -1), eligibility criteria will be checked. The Screening Visit will be 
followed by a pre-randomization visit, which should take place 1 week prior to randomization at 
V1 (Day 0/Week 1). Patients will then be randomized on a 1:1:1 basis at Visit 1 (Day 0/Week 0). 
The patients will then attend the following visits:  
• Visit 2 (Week 2) – Intermediate visit – 2 weeks after Day 0 
• Visit 3 (Week 4) – Intermediate visit – 4 weeks after Day 0 
• Visit 4 (Week 8) – Intermediate visit – 8 weeks after Day 0 
• Visit 5 (Week 12) – Final treatment period visit – 12 weeks after Day 0 
• End of Study (EOS) visit, for all patients who complete the double-blind treatment period 
(at least 16 days but not more than 30 days after Visit 5).  
• End of treatment (EOT) visit in case of premature discontinuation (at least 16 days and at 
the latest 30 days after the final administration of study drug) 
3.1. 
NUMBER OF PATIENTS 
It is planned to randomize 45 patients to either elafibranor 80 mg (15 patients) or elafibranor 120 
mg (15 patients) or placebo (15 patients) treatment in a 1:1:1 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 1:1:1 ratio: 
• Elafibranor 80 mg 
• Elafibranor 120 mg 
• Placebo 
Treatment assignments will be made using an interactive voice/web response system 
(IVRS/IWRS). 
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 a maximum of 20 weeks (screening period of up to 4 
weeks, + treatment period of up to 12 weeks, + follow-up period of 16 to 30 days) for each 
complete patient. 


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Clinical Trial GFT505B-216-1 
Protocol V3.0 04 December 2017 
GENFIT 
CONFIDENTIAL 
Page 32 of  92 
3.5. 
STUDY PERIODS AND SCHEDULE OF ASSESSMENTS  
The study will be comprised of 3 periods. The Screening Period (-4 weeks to -1 week) will 
precede a 12-week double-blind Treatment Period (Figure 1). A pre-randomization visit (to 
confirm eligibility), will take place 1 week prior to randomization at Visit 1. The study follow-up 
period will last up to 30 days after Visit 5. 
A schedule of assessment by visit is presented in Table 1, and a schedule of biological assessment 
by visit is presented in Table 2. 
3.5.1. Screening Period 
3.5.1.1. 
Screening Visit [SV] (Week -4 to Week -1)  
The following screening procedures will be performed for all potential patients at the SV 
conducted between Week -4 and Week -1 prior to Randomization: 
• Signature of informed consent witnessed by the Investigator or designated person. 
• Patient number allocation via IVRS/IWRS. 
• Check medical history/demographics. 
• Check inclusion/exclusion criteria (as described in Section 4). 
• Physical examination (described in Section 6.2.1). 
• Review dietary, fluids and recommendations (described in Section 5.1.1)  including 
alcohol restrictions. 
• Record vital signs (described in Section 6.2.2). 
• Record height and weight. 
• Check concomitant/prior medication (described in Section 7.12 and Appendix III) 
• Check AEs from time of Informed Consent Form (ICF) signature (described in Section 6 
and Section 8). 
The Screening biological assessment (SBx) will be performed at the SV. 
The following biological assessments (detailed in Table 2 will be performed at SB: 
• Blood samples (described in Table 2). 
• Urinalysis collection (dipstick will be done at central lab). 
• Urinary pregnancy test (for women of childbearing potential only [WOCBP]). 
If needed, a retesting of abnormal creatine phosphokinase (CPK) results or 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 1 and 2 (see Section 3.5.5.1 and Section 4.2). Any 
other retest deemed necessary by the Investigator should be discussed with the Study Medical 
Monitor. 
At the SVpotentially eligible patients will be  asked if they agree to participate in the study and 
sign the ICF. Preliminary entrance criteria will be reviewed. Each patient who has signed the ICF 
will be allocated a patient number composed of 7 digits which is generated by the IVRS/IWRS.   
 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. 
A specific IVRS/IWRS procedure manual will be provided to the Investigator. 


Clinical Trial GFT505B-216-1 
Protocol V3.0 04 December 2017 
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CONFIDENTIAL 
Page 33 of  92 
3.5.1.2. 
Pre-Randomization Visit [PRV] (Week -1)  
Upon receipt of the SB results or any retesting/additional testing results from the central 
laboratory, the Investigator should check the eligibility with inclusion/exclusion criteria. 
If the patient meets all inclusion criteria and none of the exclusion criteria (clinical, histological, 
and biological), the Investigator or authorized, designated Study Coordinator/Research Nurse will 
inform the patient of his/her inclusion by a phone call at least 1 week prior to the Randomization 
Visit V1. As soon as this randomization date is validated, the Investigator or authorized, 
designated Study Coordinator/Research Nurse will register immediately the patient eligibility and 
provisional randomization date in the IVRS/IWRS in order to pre-randomize the patient. When 
the IVRS/IWRS confirms the pre-randomization, it will provide the Investigator with a treatment 
number for the patient and will immediately forward the information to the drug distribution 
centre which will be responsible to send to the site the treatment allocated to the patient within 1 
week at most. 
In case of ineligibility, the patient should be contacted as soon as possible. 
3.5.2. Treatment Period (Week 0 to Week 12)  
Efficacy of elafibranor versus placebo on PBC will be evaluated in the double-blind treatment 
period of 12 weeks. 
During these 12 weeks of treatment, visits will be scheduled at Weeks 0, 2, 4, 8 and 12. Clinical 
and biological evaluation will be performed during this Treatment Period. 
3.5.2.1. 
Randomization Visit V1 (Week 0)  
Eligible patients will return to the site at the Randomization Visit (V1) and at Weeks 2, 4, 8 and 
12 during the Treatment Period of the study. The patient will be contacted at least 1 week before 
each visit to be reminded of procedures and investigational product (IP) return. 
The following will be performed only at V1: 
• Check inclusion/exclusion criteria (detailed in Section 4).  
• IVRS/IWRS 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 dietary, fluids and lifestyle recommendations (described in Section 5.1.1) 
including alcohol restrictionsCheck concomitant/prior medication (described in 
Section 7.12 and Appendix III) 
• Quality of life assessment (described in Section 6.2.4) and pruritus score 
• Check AEs 
• Study placebo or drug dispensation (described in Section 7.6) 
• Blood samples (described in Table 2) 
• Urinalysis collection (dipstick done by central lab) (described in Table 2) 
• Urinary pregnancy test (for WOCBP only) 
• 12-lead ECG (described in Section 6.2.3) 
• PK blood sampling (predose, 15 min, 30 min, 1h, 1h30, 2h, 4h, 6h and 24h postdose, see 
Section 6.1.2). 


Clinical Trial GFT505B-216-1 
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Page 34 of  92 
3.5.2.2. 
Treatment Period Visits V2 to V5 (Week 2 to Week 12)  
The following procedures will be performed at each of the 12-week visits from V2 to V5: 
• IVRS/IWRS 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 dietary, fluids and lifestyle recommendations (described in Section 5.1.1) 
including 
alcohol 
restrictionsCheck 
concomitant/prior 
medication 
(described in 
Section 7.12 and Appendix III) 
• Quality of life assessment (except  at V2) (described in Section 6.2.4) 
• Check AEs (described in Section 6 and Section 8) 
• Study placebo or drug dispensation (except at V2 and V5) (described in Section 7.6) 
• Blood samples (described in Table 2) 
• Urinalysis collection (dipstick done by central lab)(described in Table 2) 
• Urinary pregnancy test (for WOCBP only, except at V2) 
• 12-lead ECG (except at V2; described in Section 6.2.3) 
• Pruritus scale (5D-itch scale & VAS) 
• Drug accountability and compliance assessment 
• PK blood sampling only at V2 (predose, 15min, 30min, 1h, 1h30, 2h, 4h, 6h and 24h 
postdose, see Section 6.1.2). 
3.5.3. End of Treatment Visit [EOT] 
All patients who permanently discontinue their study medication prior to study completion will 
undergo an EOT Visit at least 16 days and at the latest 30 days after the final administration of 
study drug.  
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.  
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: 
• IVRS/IWRS 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 dietary, fluids and lifestyle recommendations (described in Section 5.1.1) 
including alcohol restrictionsCheck concomitant/prior medication (described in 
Section 7.12 and Appendix III) 
• Pruritus scale (5D-itch scale & VAS) 
• Quality of life assessment (described in Section 6.2.4) 
• Check AEs (described in Section 6 and Section 8) 
• Blood samples (described in Table 2) 
• Urinalysis collection (dipstick done by central lab)(described in Table 2) 
• Urinary pregnancy test (for WOCBP only)  
• 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. 


Clinical Trial GFT505B-216-1 
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Page 35 of  92 
3.5.4. End of Study Visit [EOS] 
All patients who complete the double-blind treatment period will undergo an EOS Visit at least 16 
days but not more than 30 days after Visit 5.   
The patient will be contacted at least 1 week before this visit to be reminded of procedures and 
any outstanding investigational product (IP) return (if required). The following procedures will be 
performed at the EOS Visit: 
• IVRS/IWRS 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 alcohol restrictions (described in Section 5.1.1) 
• Check concomitant/prior medication (described in Section 7.12 and Appendix III)  
• Pruritus scale (5D-itch scale & VAS) 
• Quality of life assessment 
• Review concomitant medications/prohibited medications 
• Check AEs (described in Section 6 and Section 8) 
• Blood samples (described in Table 2) 
• Urinalysis collection (dipstick performed by central lab)(described in Table 2) 
• Urinary pregnancy test (for WOCBP only) 
• Drug accountability (if required, i.e. if not completed already at Visit 5) 
• 12-lead ECG (described in Section 6.2.3) 
3.5.5. Optional Visits 
3.5.5.1. 
Retesting Screening Visits 
Upon receipt of results from biological assessment done at SV, 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 SV are:  
• CPK:  can be repeated prior to Pre-Randomization Visit (PRV)..  
• HCV RNA testing, in case positive HCV Ab test: required latest 2 weeks prior to 
Randomization (V1) (meaning at least one week prior to pre-Randomization).  In case of 
known cured HCV infection, HCV RNA testing can be done at SV without waiting for 
HCV Ab results. 
Any other screening period retest deemed necessary by the Investigator should be discussed with 
the Study Medical Monitor. 
3.5.5.2. 
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 (such as abdominal imaging in case of elevation of lipase or amylase) 
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.). 


Clinical Trial GFT505B-216-1 
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Unscheduled visits will be needed for patients who may require further follow-up due to safety. 


Clinical Trial GFT505B-216-1 
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Table 1: Study General Assessment Schedule  
 
Screening 
period 
Treatment period 
Follow-
up 
period 
Visit 
SV 
V1 
V1 
(PK) 
V2 
V2 
(PK) 
V3 
V4 
V5 
EOT g 
EOS 
Week 
[-4,-1] 
0 
 
2 
 
4 
8 
12 
16 to 30 
days 
after 
last 
drug 
intake 
16 
to 
30 days 
after 
V5 
Day 
[-28, -7] 
0 
 
14 
 
28 
56 
84 
 
100-
114 
Permitted Margin 
 
0 
 
14 +/- 
1 day  
28 +/- 
2 days 
28 +/- 
2 days 
28 +/- 
2 days  
16 + 14 
days 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history / 
demographics 
X 
 
 
 
 
 
 
 
 
 
Check inclusion / 
exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signs & heightb & 
weight measurement 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
12-Lead ECG 
 
X 
 
 
 
X 
X 
X 
X 
X 
Lab evaluation (see table 
“study biological 
assessment schedule”) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
PK blood samplingc 
 
X 
Xd 
X 
Xd 
 
 
 
 
 
Pre-randomization 
Xe 
 
 
 
 
 
 
 
 
 
Phone call to the patient 
 
Xf 
 
X 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
IVRS/IWRS registration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review prior/concomitant/ 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus scoring (5D itch 
scale & VAS) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Quality of life 
questionnaire (PBC40) 
 
X 
 
 
 
X 
X 
X 
X 
X 
Study placebo or drug 
dispensation 
 
X 
 
 
 
X 
X 
 
 
 
Drug accountability and 
compliance assessment 
 
 
 
X 
 
X 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram; IVRS/IWRS = integrated voice/web response system; PK = pharmacokinetic; SV = 
screening visit; V = visit.  
a 
All inclusion/exclusion criteria, including biological and histological criteria, assessed at V1 
b 
Height is measured only at SV 
c 
There are a total of 9 PK sampling time point:  8 each at V1 and V2; the 9th sample is taken at 24h on the following day 
(V1(PK) and V2(PK), respectively). 
d 
24 h sampling timepoint to be done at ambulatory visit (pre-dose, fasting) 
e 
At least 1 week before visit V1 and after eligibility confirmation  
f 
A pre-randomization confirmation  
g 
only in case of premature discontinuation, EOT needs to be performed 
 


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Table 2: Study Biological Assessment Schedule  
 
Screening 
period 
Treatment period 
Follow-
up period 
Visit 
SV 
SBx 
V1 
Bx1 
V2 
Bx2 
V3 
Bx3 
V4 
Bx4 
V5 
Bx5 
EOTc 
BEOT 
EOS 
Week 
[-4,-1] 
0 
2 
4 
8 
12 
16 to 30  
days 
after last 
drug 
intake 
16 to 30 
days 
after V 5 
Labs - Haematology 
haemoglobin, haematocrit, RBC, WBC, 
differential count, platelet count, 
prothrombin time, reticulocytes count 
X 
X 
X 
X 
X 
X 
X 
X 
Labs- Urinary Pregnancy testa 
X 
X 
 
X 
X 
X 
X 
X 
Labs – Serology 
HIV Ab I/II, HBsAg and HCV Ab (HCV 
RNA in case HCV Ab>0,  
X 
 
 
 
 
 
 
 
Labs – Biochemistry 
 
 
 
 
 
 
 
 
Special B1: alkaline phosphatase, ALT, 
AST, GGT, CPK, 5’ nucleotidase, total and 
conjugated bilirubin, albumin, creatinine, 
eGFR, sodium, MELD-score 
X 
 
 
 
 
 
 
 
Total: alkaline phosphatase, ALT, AST, 
GGT, CPK, 5 nucleotidase, total and 
conjugated bilirubin, creatinine, eGFR,  
total proteins, albumin, electrolytes 
(sodium, potassium, chloride, calcium), 
hsCRP, fibrinogen, haptoglobin, lipase, 
amylase   
 
X 
X 
X 
X 
X 
X 
X 
Labs – Lipids 
 
 
 
 
 
 
 
 
Total Cholesterol, HDL-C, TG, LDL-C 
 
X 
X 
X 
X 
X 
X 
X 
Inflammatory markers 
TNF-α, TGF-β, IL-6, PAI-1  
 
X 
 
 
 
X 
X 
X 
Other 
IgM, urinary myoglobin b 
 
X 
 
 
 
X 
X 
X 
Liver markers: 
CK18 (M65 & M30), lysiphosphatidic acid, 
C4, FGF19, bile acidsd 
 
X 
 
 
 
X 
X 
X 
Labs – Urinalysis (dipstick done by 
central lab) 
Specific gravity, pH, protein, glucose, 
ketones, bilirubin, urobilinogen, blood, 
nitrite, leukocytes 
X 
X 
X 
X 
X 
X 
X 
X 
Safety markers 
Serum Cystatin C 
Urinary albumin, urinary creatinine, urinary 
ACR 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ACR = albumin/creatinine ratio; B = biological assessment visit; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; CPK = creatine phosphokinase; GGT = gamma-glutamyl transferase; eGFR = estimated glomerular filtration 
rate; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MELD = model end stage liver 
disease; RBC = red blood cell; TG = triglyceride; V = visit; WBC = white blood cell.  
a 
for Women of Childbearing potential only (WOCBP)  
b 
assessment of presence of myoglobin in urine may be done locally at the discretion of the PI, only in case of clinically 
significant CPK elevation 
c 
in case of premature discontinuation, end of treatment visit should be performed between 16 and 30 days after last drug intake 
d 
Bile acid panel includes the following:  (cholic acid (CA), glycocholic acid (GCA), taurocholic acid (TCA), chenodeoxycholic 
acid (CDCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid (TCDCA), deoxycholic acid (DCA), 
glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), lithocholic acid (LCA), glycolithocholic acid (GLCA), 
taurolithocholic acid (TLCA), ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid 
(TUDCA), hyocholic acid (HCA), glycohyocholic acid (GHCA), taurohyocholic acid (THCA), hyodeoxycholic acid (HDCA), 
glycohyodeoxycholic acid (GHDCA) and taurohyodeoxycholic acid (THDCA). 
 


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4. 
PATIENT SELECTION 
4.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial: 
1. Must have provided written informed consent (IC) 
2. Males or females 18 to 75 years of age 
3. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the 
following 3 diagnostic factors: 
o History of elevated ALP levels for at least 6 months  
o Positive 
Anti-Mitochondrial 
Antibodies 
(AMA) 
titers 
(> 1/40 
on 
immunofluorescence or M2 positive by enzyme-linked immunosorbent assay 
[ELISA]) or positive PBC-specific antinuclear antibodies  
o Liver biopsy consistent with PBC 
4. ALP ≥ 1.67x upper limit of normal (ULN) (‘inadequate response to UDCA’)   
5. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit  
6. Contraception: Females participating in this study must be of non-childbearing potential or 
must be using highly efficient contraception for the full duration of the study and for 
1 month after the end of treatment, as described below: 
a) Cessation of menses for at least 12 months due to ovarian failure 
b) Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically 
documented ovarian failure 
c) Using a highly effective non-hormonal method of contraception (bilateral tubal 
occlusion, vasectomised partner or intra-uterine device) 
d) 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. 
7. Must agree to comply with the trial protocol. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from entering the study: 
1. History or presence of other concomitant liver diseases including: 
• Positive hepatitis B surface antigen (HBsAg) at Screening 
• Positive HCV RNA  (tested for in case of known cured HCV infection, or positive 
HCV Ab at Screening) 
• Alcoholic liver disease 
• Primary sclerosing cholangitis (PSC) 


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• Definite autoimmune hepatitis (AIH), or ‘AIH-PBC overlap syndrome’; (the existence 
of) AIH is defined as continuing use of budesonide or other systemic corticosteroid 
theray, and/or azathioprine, and/or other immunosuppressive therapy following an 
historical AIH diagnosis (EASL 2015). ‘AIH-PBC overlap syndrome’ is based upon 
fulfilment of the Paris criteria (Chazouilléres 1998)for both AIH (ALT ≥5x ULN; IgG 
≥2x ULN or smooth muscle antibody; interface hepatitis), and PBC (ALP ≥2x ULN; 
AMA, and non-suppurative bile duct injury/destruction),, and requiring corticosteroid 
therapy for disease management, either currently or in the past. 
• Biopsy confirmed Nonalcoholic Steatohepatitis NASH) 
• Known history of alpha-1 antitrypsin deficiency, or other metabolic forms of chronic 
liver disease. 
• Gilbert's Syndrome (due to interpretability of bilirubin levels) 
2. Screening CPK > ULN 
3. Screening ALT or AST > 5 ULN 
4. Screening total bilirubin > 2 ULN 
5. Screening serum creatinine > 1.5 mg/dl and eGFR < 60 mL/min/1.73 m2,  
6. Significant renal disease, including nephritic syndrome, chronic kidney disease  
7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh class B, C).   
8. Platelet count <150 X 10 3/microliter 
9. Albumin <3.5 g/dL 
10. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including: 
• Current Model for End-Stage Liver Disease score ≥15; current placement on a liver 
transplant waiting list, or history of undergoing liver transplantation.  
• Any record of complications of cirrhosis and/or portal hypertension such as: 
o Gastroesophageal variceal bleeding and endoscopic therapy and/or transjugular 
intrahepatic portosystemic shunt [TIPS] insertion 
o Ascites formation requiring intervention, e.g. diuretic therapy 
o Spontaneous bacterial peritonitis 
o Hepatic encephalopathy  
o Confirmed or suspected hepatocellular carcinoma 
11. Hepatorenal syndrome (type I or II) Administration of the following medications is 
prohibited as specified below: 
• From pre-randomization to EOT or V5 visit : indomethacin 
• 2 months preceding screening throughout the trial (up to last study visit) : fibrates or 
obeticholic acid, thiazoledinediones (glitazones) 
• 3 months prior to screening and throughout the trial (up to last study visit) : 
azathioprine, 
colchicine, 
cyclosporine, 
methotrexate, 
mycophenolate 
mofetil, 
pentoxifylline; budesonide and other chronic systemic corticosteroids; and potentially 
hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or 
nitrofurantoin) 


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• 12 months prior to inclusion visit and throughout the trial (up to last study visit): 
antibodies or immunotherapy directed against interleukins or other cytokines or 
chemokines 
NOTE : Anti-pruritus treatment, including rifamycin, is allowed if prescribed for at least 6 
months prior to screening, and on stable dose at least 3 months prior to screening. and 
continues at the same dose throughout the study 
12. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a 
positive serum pregnancy test), or lactating 
13. Known history of human immunodeficiency virus (HIV) infection 
14. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)  
15. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the trial 
16. Anticipated changes to current medications (that will be continued) during the course of 
the trial 
17. History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day 
for men, and more than 20 g pure alcohol per day for women, or other substance abuse 
within 1 year prior to Day 0 (randomization visit) 
18. Participation in another trial with an investigational drug, biologic, or medical device using 
active substance within 30 days prior to screening, or within 5 ½ lives of the active 
substance, whichever is longer. 
19. History of noncompliance with medical regimens, or patients who are considered to be 
potentially unreliable. 
20. Mental instability or incompetence, such that the validity of informed consent or 
compliance with the trial is uncertain. 
21. Known hypersensitivity to the investigational product or any of its formulation excipients. 
22. Evidence of any other unstable or untreated clinically significant immunological, 
endocrine, hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease. 


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5. 
TRIAL PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (Table 1 and 
Figure 1) and in Section 3.5. 
The Investigator will be asked, whenever possible, to schedule patient visits at the same time of 
the day for each patient. A patient may be seen at any time for reasons of safety. 
During each visit, dietary, fluid and 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 SV are described in Section 5.2. 
5.1. 
STUDY RECOMMENDATIONS 
5.1.1. Dietary, Fluid, and Lifestyle Restrictions 
The following restrictions should be applied to patients in this trial from Screening 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 (i.e., at each study visit). As such, patients should not consume 
any breakfast or take any medication (including study medication) in the morning prior to 
blood sampling. In case the patients do not fast before a visit, a new appointment will be 
scheduled within 2 days. 
• Urine will be collected at each visit.   
• 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). 
• On visits with PK assessment, study treatment will be taken after the blood sampling for 
biological assessment and PK predose sampling.  If possible, patient should remain fasting 
for 90 minutes after dosing. 
• During the 48 hours preceding each study visit, patients should not perform strenuous 
exercise. 
• 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). 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, whisky). 
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). 


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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 study 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: 
• 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 study Medical Monitor prior to making such a 
decision 
• Non-permitted concomitant medication (described in Section 7.12 and Appendix III) 
• 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 at least 16 days but no more than 30 days after the last administration of study 
drug (described in Section 3.5.3). 
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 only if the patient withdraws consent, or if enrolling in any other clinical trial involving 
an IP, or enrolling in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
At the time of discontinuing from the study, the Medical Monitor and IVRS/IWRS should be 
contacted, and, if possible, an EOT Visit should be conducted (see Section 3.5.3). The patient will 
be permanently discontinued from the study at that time with no further follow-up. The date the 
patient is withdrawn from the study and the reason for withdrawal should be appropriately 
documented in the eCRF. 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.  Survival status will be collected within legal and 
ethical boundaries for all patients randomized, including those who did not get study drug. 
Survival status will be searched in public sources during the study close-out period. If survival 
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, or at the discretion of the Sponsor. In 
addition, the Sponsor retains the right to discontinue development of the study drug 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 
Patient Rescreening 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 rescreening, 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. Biological Assessments 
All blood and urine samples for efficacy and/or for safety assessment (as described in Table 2) 
will be returned and analyzed by the central laboratory (BARC: Ghent – Belgium, or New York – 
USA). 
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 CPK, and HCV RNA (in 
case of positive HCV Ab at screening visit, or known cured HCV infection) as described 
Section 3.5.5.1. Any other retest deemed necessary by the Investigator should be discussed with 
the Study Medical Monitors. 
6.1.1.1. 
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 done at central lab) 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 chemistry panel will be measured. 
The total chemistry panel and urine analysis will be measured at all visits from V1 to EOT orEOS 
visits respectively. 
6.1.1.2. 
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.  
6.1.1.3. 
Serology (SB1) 
Screening for a hepatitis panel and HIV antibodies will be performed at SV and include: 
• HIV Ab I/II 
• HBsAg 


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• HCV Ab (positive HCV RNA in case HCV Ab > 0 to be performed at Retesting Screening 
Visit or at screening visit if known cured hepatitis C virus infection) 
6.1.1.4. 
Other Parameters 
Other markers will be measured as described in Table 2.  
6.1.2. Pharmacokinetics Evaluation 
6.1.2.1. 
Description of Pharmacokinetic Evaluation Parameters 
The aim of the PK section of the study is to assess the pharmacokinetic profile of elafibranor in 
patients with PBC. 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at 
9 timepoints at V1 and after 2 weeks of repeated once daily exposure (V2). 
6.1.2.2. 
Pharmacokinetic Analysis 
The PK analysis 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). 
6.1.2.3. 
Pharmacokinetic Blood Sampling Timepoints 
Blood sampling will be performed for elafibranor and its main active metabolite GFT1007 plasma 
concentration ,, at the following timepoints (predose and 15min, 30 min, 1h, 1h30, 2h, 4h, 6h, and 
24 post dosing) at V1 and at steady-state after 2 weeks of treatment (V2).  Allowable windows for 
PK sample collection follow.  Samples outside of the allowable windows will be a protocol 
deviation, but should still be collected and sent to central lab for analysis. 
Timepoint 
Allowable Window 
Predose 
0 min 
15 min 
0 min 
30 min 
0 min 
1 hour 
0 min 
1 hour 30 min 
10 min 
2 hours 
10 min 
4 hours 
10 min 
6 hours 
10 min 
24 hours 
10 min 
 
6.1.2.4. 
Pharmacokinetic Blood Handling Procedures 
Blood samples will be collected into one 6 mL lithium heparin Vacutainer® tube . The samples 
must be protected from light, e.g.: wrapped in aluminum foil, 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 


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plasma will be dispensed in a polypropylene opaque tube for aliquot 1, and 1.5 mL of plasma for 
aliquot 2. The plasma samples will be stored at –70°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 for analysis. 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. Physical Examination 
A physical examination will be performed by a qualified medical professional, and weight 
measured at each visit. Height will be measured at the Screening Visit only. 
6.2.2. Vital Signs 
Blood pressure (mmHg) and pulse rate (beats per minute) will be measured at each visit according 
to the “Recommendations for Blood Pressure Measurement in Humans and Experimental 
Animals” published in an American Heart Association scientific statement. 
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. 
6.2.3. Electrocardiogram 
A standard 12-lead ECG will be obtained at V1, 3, 4, 5 and EOT or EOS Visits.  
Electrocardiograms will be recorded using 12-lead ECG recorders. 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. Patient Reported Outcomes Questionnaires 
A standardized and validated questionnaire for quality of life (PBC 40QOL) will be completed by 
patients at V1, V3, V4, V5 and EOS or EOT Visits respectively. In addition, patients will 
complete the 5D Itch scale and the Visual Analog Scale (VAS) at these visits.   
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION 
RULES 
6.3.1. Creatine Phosphokinase 
If at any visit during the treatment period, a patient experiences diffuse myalgia, muscle 
tenderness, and/or marked increase in muscle CPK values between 3 x and 5 x ULN (≥ 3 x ULN 
and ≤ 5 ULN), an unscheduled site visit and test must be performed within 48 to 72 hours, and an 
assessment of myoglobinuria may be done locally. 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 (≥ 3 x ULN and ≤ 5 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 period, 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 
Rules for liver monitoring and for discontinuation in case of liver biochemical test elevations are 
described below.  
6.3.2.1. 
Monitoring of Patients With Normal Baseline Aminotransferase Values 
Liver function monitoring requirements for patients with normal baseline ALT and AST  at V1: 
• Increase in ALT or AST to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours 
 
If during the following retest: 
o ALT or AST remains >3 x ULN but ≤5 x ULN: continue the drug with close 
serial monitoring  (once a week) 
o ALT or AST increases to >5 x ULN: permanently discontinue patient from study 
drug and schedule EOT Visit  
• Increase in ALT or AST >5 x ULN: retest after 48 to 72 hours 
If during the following retest: 
o ALT or AST remains >5 x ULN: permanently discontinue patient from study drug 
and schedule EOT Visit  
o ALT and AST reduces to ≤5 x ULN: continue the drug with close serial 
monitoring (once a week). 
• Increase in ALT or AST >3 x ULN AND increase in total bilirubin > 2 ULN : permanently 
discontinue patient from study drug and schedule EOT Visit  
• Increase in ALT or AST >3 x ULN AND increase in INR>1.5: permanently discontinue 
patient from study drug and schedule EOT Visit  
• Increase in ALT or AST >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  
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: 
• Increase in ALT or AST to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours 
o ALT or AST remains >3 x baseline value but ≤ 10 x ULN: continue the drug with 
close serial monitoring (once a week) 
o ALT or AST increases > 5 x baseline value or >10 x ULN: permanently 
discontinue patient from study drug and schedule EOT Visit  
• Increase in ALT or AST >3 x baseline value AND increase in total bilirubin > 2 ULN: 
permanently discontinue patient from study drug and schedule EOT Visit  
• Increase in ALT or AST >3 x  baseline value AND increase in INR>1.5: permanently 
discontinue patient from study drug and schedule EOT Visit  


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• Increase in ALT or AST >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  
6.3.3. Specific Biological Monitoring  
At any visit, if a patient experiences clinically significant lipase and/or amylase elevations, 
imaging CT Scan may be performed for the diagnosis of pancreatitis. 
 
6.3.4. Safety and Efficacy Data Review 
Data Safety Monitoring Board (DSMB): Not applicable. 
A DMSB was not specifically set-up for this study for the following reasons: 
- 
The study is conducted in a small number of participants, for a short duration 
- 
GFT505 showed in previous clinical studies a very good safety profile 
The medical monitors will assist the investigators for all medical matters, whenever required, and 
will make sure that they respect the Protocol and the study procedures, including reporting of 
adverse events. 
6.3.5. Guidance for Investigators 
Summary of safety data (for completed studies only) 
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 


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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). 
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 (MTD), numbers and percentages of frequency of non serious 
adverse drug reactions (AR, adverse events 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 thus summarized in Table 3. 
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)  


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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  
Decreased 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 drug induced 
liver injury (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 


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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. 
 
Conclusion 
Based on the cumulative experience gathered to date, gastro-intestinal disorders such as diarrhea 
and vomiting, and asthenia or fatigue are considered common non serious 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. 


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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 80 mg or 120 mg white to off-white round 
coated tablets (of different size) with no printed inscription. The tablet contains elafibranor and 
inactive ingredients (microcrystalline cellulose, povidone, croscarmellose, anhydrous colloidal 
silica, magnesium stearate, Opadry II HP 85F18422). 
Two Placebo tablets  (each one of same size as corresponding active tablet) to match elafibranor 
80 mg or 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 will be packed in child proof wallets. 
Each childproof wallet will contain 2 tablets (one of each size), containing either one active tablet 
and one placebo tablet or two placebo tablets to ensure the blind between the treatment arms.  
Thirty-five wallets of two tablets will be packaged inside a period box. Three period boxes will be 
packaged into a carton. 
7.2.2. Labeling 
All labels for study drugs will 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. 
 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take two tablets per day of elafibranor 80 mg or 120 mg or placebo 
orally before breakfast with a glass of water each morning. 


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7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP 
If the patient fulfills all criteria to enter the treatment period, the Investigator or authorized, 
designated study coordinator/research nurse will register the patient in the IVRS/IWRS system to 
pre-randomize him/her (at least 1 week before V1). 
The 
IVRS/IWRS 
will 
check 
if 
the 
Investigator 
or 
authorized, 
designated 
study 
coordinator/research nurse is is authorized to use the system (identification number and access 
code). The IVRS/IWRS will then allocate the patient to a treatment group (placebo or elafibranor 
80 mg or 120 mg) through a treatment number and will immediately forward the information to 
the Drug Distribution Centre which will be responsible to send to the site the corresponding 
treatment package allocated to the patient for the 12-week period, within 1 week at most. This 
labeled package will include 3 period boxes, one for each period [V1-V3], [V3-V4], and [V4-V5]. 
A confirmatory email will also be sent to the Investigator or authorized, designated study 
coordinator/research nurse, and to the Sponsor. The pharmacy will acknowledge receipt of the 
study drug in the IVRS/IWRS. 
A specific IVRS/IWRS procedure manual will be provided to the pharmacy. 
The randomization list will be generated by the IVRS/IWRS partner and will be kept under 
blinded 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 
The Investigator will receive one package per randomized patient, each package covering the full 
treatment period: 
• Upon pre-randomization of each patient: the Investigator will receive a 1st package 
containing 3 period boxes (one for each of periods V1-V3, V3-V4 and V4-V5) 
Each randomized patient will be given at each visit from V1 to V4 (except at V2) the study 
medication containing the adequate number of tablets to cover the drug administration over the 
entire period (i.e. covering at least 4 weeks of treatment + 5 days margin for each period): 
• At Visit 1: the Investigator will dispense 1 labeled period boxes of 35 wallets of 2 tablets  
• At Visit 3: the Investigator will dispense 1 labeled period boxes of 35 wallets of 2 tablets  
• At Visit 4: the Investigator will dispense 1 labeled period boxes of 35 wallets of 2 tablets  
• The patient will be instructed to take the treatment orally (2 tablets per day before 
breakfast) with a glass of water. 
The Investigator will confirm each study drug dispensation in the IVRS/IWRS. A specific 
IVRS/IWRS procedure manual will be provided to the Investigator. 
7.7. 
TREATMENT REPLACEMENT 
Treatment replacement, if needed, will be explained in details in a specific IVRS/IWRS procedure 
manual which will be provided to the Investigator. 


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7.8. 
PROCEDURE FOR BLINDING 
The Investigator, patient, and study personnel will be blinded to the treatment. Both elafibranor 
and placebo tablets and packaging are indistinguishable. 
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, eligible patients will be 
randomly assigned to active treatment (elafibranor 80 or120 mg) or placebo at the pre-
randomization visit. 
 
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 IVRS/IWRS. The Investigator will be able to unblind any treatment 
carton that was dispensed to the patient by connecting to the IVRS/IWRS (24-hour and 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 IVRS/IWRS will verify the authorization to unblind the entered treatment carton 
number 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 Visit 1 and at every subsequent 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 recorded 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. 


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If drug is destroyed at the site, the Investigator must maintain accurate records for treatment 
cartons destroyed recording: 
• Treatment carton (kit) number (see Appendix V) 
• Quantity destroyed 
• Method of destruction 
• Person who disposed of the drug 
• Date of destruction 
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. 
Similarly, any qualitative or quantitative change in concomitant therapy should be avoided, when 
possible (see Table 4 and Appendix III). In the event such a change becomes necessary during the 
study, it should be recorded by the Investigator in the eCRF (including concomitant medications 
taken within 30 days 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 4 and Appendix III. 
The following medications are not allowed within the timeframe given in Appendix III: 
• Thiazoledinediones (glitazones [pioglitazone & rosiglitazone]) 
• Obeticholic acid 
• Fibrates 
• Budesonide and other systemic corticosteroids 
• Azathioprine 
• Colchicine 
• Cyclosporine 
• Methotrexate 
• Mycophenolate mofetilPentoxyfilline 
• Potentially hepatotoxic drugs (alpha-methyl-dopa, sodium valproic acid, isoniazide, 
nitrofurantoin) 
• Antibodies or immunotherapy directed against interleukins or other cytokines or 
chemokines 
• Indomethacin (NOTE: Other NSAIDs are allowed) 
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). 
7.12.3. Permitted Medication Under Conditions 
See Table 5 and Appendix III. 


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The following medications are permitted under the condition of steady dosage prior to Screening: 
• Ursodeoxycholic acid if taken for at least 12 months (and stable dose for ≥ 6 months) 
prior to screening visit 
• Statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to 
Screening 
• Rifamycin and other anti-pruritis medication, if taken for at least 6 months prior to 
screening, and at stable dose for the 3 months prior to screening. 
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 Drug-Drug Interactions. 
In the event that additional concomitant therapy becomes necessary during the study (treatment 
and follow-up periods) , it 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 Food and Drug Administration (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 consent form is signed. Such a 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 
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 


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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) 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. Visits to the ER 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..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 


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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 
• 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. 
8.1.4. 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 causally 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. 


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8.2. 
ASSESSMENTS 
The Investigator will establish whether or not any AEs have occurred at each visit from the date of 
consent through the EOS/EOT visit (or 30 days after the last drug intake whichever is later). 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: 
• 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 IP 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: 


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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 
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 EOS/EOT visit (or 30 days after last drug 
intake, whichever is later). 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 EOS/EOT visit (or 30 days after last drug intake, whichever is later). 
8.3.2. Reporting a Serious Adverse Event 
Serious AE reporting begins from signature of the patient ICF and ends at the EOS/EOT visit (or 
30 days after last drug intake, whichever is later). 
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. 
Investigators must notify, by fax or e-mail, the Sponsor designated representative SGS Life 
Science Services (LSS) Medical Affairs 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 SGS LSS 
MEDICAL AFFAIRS AT THE FOLLOWING FAX NUMBERS: 
FAX numbers: +32 (0)15 29 93 94 or 1-800-746-6618 
Contact Person: SGS LSS Medical Affairs Department 
E-mail: be.life.saefax-ma@sgs.com 
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 SGS LSS Medical Affairs 
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 SGS LSS 
Medical Affairs 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) 
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. 


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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, even if this goes beyond the EOS orEOT visit. 
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. 
8.6.1. Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to SGS LSS Medical 
Affairs 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 SGS LSS Medical Affairs 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. 


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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. 
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. Unless 
stated otherwise, statistical tests will be 2-sided and use a 5% significance level, leading to 95% 
(2-sided) confidence intervals (CIs). No adjustment for multiplicity will be made for the primary 
and secondary efficacy variables. 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.  
Descriptive summary statistics for continuous variables will include the number of patients, mean, 
standard deviation (SD), median, and range.  Descriptive summary statistics for categorical 
variables will include frequency counts and percentages.  Unless stated otherwise, the 
denominator for percentage calculations will be the number of patients with non-missing data. 
Descriptive statistics will be reported for the primary and all secondary endpoints. 
9.1. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 3 treatment groups (elafibranor 80 mg, 120 mg and 
placebo) in a 1:1:1 ratio. 
Details regarding the randomization process are in Section 3.2. 
9.2. 
ENDPOINTS 
9.2.1. Primary Endpoint 
The primary endpoint of the study is to evaluate the efficacy of elafibranor 80 mg or 120 mg with 
respect to relative change from baseline in serum ALP levels compared to placebo. 
9.2.2. Secondary Endpoints 
The secondary endpoints are to assess at Week 12: 
• Response to treatment based on composite endpoints: 
o ALP < 1.67 × ULN and total bilirubin within normal limit and > 15% decrease in 
ALP 
o ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease in ALP 
• Response according to Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score 
• Response to treatment on normalization of ALP 
• Response to treatment on normalization of bilirubin 
• Response to treatment on normalization of albumin 
• Response on 10%, 20%, 40% decrease in ALP  
• Change from baseline in ALT, AST, GGT, 5’nucleotidase, total bilirubin, conjugated 
bilirubin, albumin 
• Change from baseline in lipid parameters 
• Change from baseline in bile acids 
• Change from baseline in C4, FGF19 
• Change from baseline in IgM 
• Change from baseline in inflammatory and liver fibrosis markers 
• Change from baseline in pruritus (through 5D-itch scale & visual analogue score VAS) 


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• Change from baseline in Quality of Life (using PBC 40 questionnaire) 
• Adverse Events (AEs) 
• Cardiovascular parameters (12-lead ECG, heart rate, blood pressure) 
• Hematology and safety parameters 
9.2.3. Exploratory Endpoint 
The exploratory endpoint is to determine PK parameters of elafibranor (GFT505) and its 
metabolite GFT1007 at two daily doses 80 mg and 120 mg in patients with PBC and explore an 
exposure-response relationship. 
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 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. All ITT-
based analyses will group patients according to the treatment they were randomized to 
regardless of the treatment received during the course of the study. 
• Safety set (SS): all randomized patients who receive at least 1 dose of study drug. This set 
will be used to summarize safety. 
• Per protocol set (PPS): all 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. 
All analyses using the PPS will group patients according to the treatment actually received. 
• PK set (PKS): 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 will be analyzed based on randomized treatment. Patients in the SS or PKS 
will be analyzed based on actual treatment received. 
9.4. 
ANALYSIS OF PRIMARY ENDPOINT 
9.4.1. Reduction in Serum Alkaline Phosphatase 
Percent change in ALP levels between baseline and end-point will be computed as follows:  
[(End-point value – Baseline Value) / Baseline value)] x 100.  
Baseline value will be computed as value at randomization visit (V1). 
End-point will be computed as: 
 Value at visit V5 or 
 Value at EOT (must be post baseline value) if patient prematurely dropped out 


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The laboratory value used for calculation will be the first value (and not the retest value) in order 
to reduce the delay between last study drug intake and specimen date collection. 
The primary analysis elafibranor’s effect on ALP changes will be performed using a 
randomization-based analysis of covariance method with an adjustment for the baseline ALP level 
(LaVange, Durham and Koch, 2005).  A supportive analysis of elafibranor’s effect on ALP 
changes will be conducted based on an Analysis of Covariance (ANCOVA) model, with 
percentage change in ALP as the response variable and with the treatment group and baseline ALP 
level as explanatory variables. If there are baseline imbalances that are deemed to be important in 
influencing the relative change of ALP due to random chance, the corresponding variables may be 
added as further explanatory variables in the primary and supportive models. The analyses will be 
carried out based on the ITT population and, in addition, analyses based on the PPS population 
will be performed. 
9.5. 
OTHER STATISTICAL ANALYSIS 
9.5.1. Secondary Endpoints 
The differences in proportions or rates among the three treatment arms with respect to responses 
to composite endpoints, risk scores, normalization of bilirubin and albumin will be tested using 
the Fisher Exact Test.  If there are important baseline imbalances that occurred by chance, these 
confounding factors may be added into a binomial regression model (Spiegelman and Hertzmark, 
2005) to compare the differences in proportions among the three arms in the study. 
Continuous endpoints, including changes from baseline in laboratory parameters (including lipid 
parameters), inflammatory and liver fibrosis markers, will be examined using an ANCOVA model 
similar to that used in the analysis of the primary endpoint, i.e., the change in the variable of 
interest will be included as the response variable whereas the treatment group and baseline level of 
the variable will be included as explanatory variables.  If there are important baseline imbalances 
that occurred by chance, these confounding factors may be added into the model. 
For other items such as change in baseline in pruritus or QOL, only the descriptive statistics will 
be presented. 
The analyses defined above will be performed based on the ITT population with additional 
analyses based on the PPS population. 
Further details will be in the SAP. 
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.  
Statistical testing for all other secondary endpoints will be of exploratory nature. 
9.7. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in PASS 13 software. 
9.7.1. Reduction in ALP 
It is planned to randomized 15 patients per treatment group.  


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Fifteen patients each in elafibranor arms and placebo arm or 45 patients in total would achieve 
more than 80% power to detect a percentage difference of -20% for each dose-placebo 
comparison. This calculation assumes that the standard deviation (on the % of relative change 
from baseline) in each elafibranor arm is 18 and for placebo arm is 15 and were based on the 
results from the phase 2B elafibranor trial. The significance level (alpha) is 0.05 and test is based 
on two-sided two-sample unequal-variance t-test.  
9.8. 
PHARMACOKINETIC ANALYSIS 
Pharmacokinetic measurements: AUC024 and Cmax will be analysed for elafibranor and 
GFT1007 (main metabolite). 
Pharmacokinetic parameters of elafibranor and GFT1007 will be summarized by mean, standard 
deviation, coefficient of variation, minimum and maximum, and median. 
An exposure-response relationship will be explored. 
9.9. 
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 
Safety Set.  
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 written for all 
SAEs. 
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 
12 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. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment 
group using descriptive statistics.  


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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 PBC-40 or pruritus score which will be collected in paper. 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. 
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 IP. 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. 


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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) 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 the CRO 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. 
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. 
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), 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 


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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 one 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. 
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. 


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In the case of any exploratory sub-studies, 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. 
12.5. DEFINITION OF THE END OF THE RESEARCH 
End of the research corresponds to the end of participation (EOS or  EOT Visit respectively) 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. 
The CRO will prepare an integrated clinical and safety report. Prior to issuing the final CSR, the 
CRO 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 the CRO. 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 CRFs (or copies of these), or in the form of a 
report, 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 


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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 
Al-Harthy N, Kumagi T. Natural history and management of primary biliary cirrhosis. Hepatic 
Medicine: Evidence and Research. 2012;4:61-71. 
Ali A, Byrne T, Lindor K. Orphan drugs in development for primary biliary cirrhosis: challenges 
and progress. Orphan Drugs: Research and Reviews. 2015;5:83-97 
Beuers U, Lindor K. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011; 55: 1178-1180. 
Boonstra K, Beuers U, Ponsioen C. Epidemiology of primary sclerosing cholangitis and primary 
biliary cirrhosis: A systematic review. J Hepatol. 2012; 56:1181-1188 
Carbone M, Mells G, Pells G, et al. Sex and age are determinants of the clinical phenotype of 
primary 
biliary 
cirrhosis 
and 
response 
to 
ursodeoxycholic 
acid. 
Gastroenterology 
2013;144:560-569. 
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. 
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 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48:871-877 
Crosignani A, Battezzati M, Invernizzi P, et al. Clinical features and management of primary 
biliary cirrhosis. World J Gastroenterol. 2008;14:3313-3327. 
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management 
of cholestatic liver diseases. J Hepatol. 2009;51:237-267. 
Giannini E, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 
2005;172:367-379. 
Ghonem N, Assis D, Boyer J. On fibrates and cholestasis: a review. Hepatology. 
2015;62:635-643. 
Hirschfield G, Gershwin E. The immunobiology and pathophysiology of primary biliary cirrhosis. 
Annu Rev Pathol. 2013;8:303-330 
Hirschfield GM, Mason A, Luketic V et al. Efficacy of obeticholic acid in patients with primary 
biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015 
Apr;148(4):751-61. 
Kim W, Lindor K, Locke G. Epidemiology and natural history of primary biliary cirrhosis in a 
U.S. community. Gastroenterology 2000;119:1631-1636. 
Kumagi T, Heathcote E. Primary biliary cirrhosis. Orphanet J of Rare Diseases. 2008;3:1. 


Clinical Trial GFT505B-216-1 
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CONFIDENTIAL 
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Kuiper EM, Hansen BE, Adang RP, et al. Relatively high risk for hepatocellular carcinoma in 
patients with primary biliary cirrhosis not responding to ursodeoxycholic acid. Eur J Gastroenterol 
Hepatol. 2010;22:1495-1502 
LaVange L, Durham T, Koch G. Randomization-based nonparametric methods for the analysis of 
multicentre trials. Statistical Methods in Medical Research. 2005; 14:281-301. 
Lens S, Leoz M, Nazal L, et al. Bezafibrate normalizes alkaline phosphatase in primary biliary 
cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 2014;34:197-203 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin 
are surrogate end points of outcomes of patient with primary biliary cirrhosis: an international 
follow-up study. Gastroenterology. 2014; 147(6):1338-49. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. American Association for 
the Study of Liver Disease (AASLD) Practice Guidelines. 2009;50(1):291-308. 
Rudic J, Poropat G, Krstic M, et al. Ursodeoxycholic acid for primary biliary cirrhosis (review). 
The Cochrane Library. 2012, Issue 12. 
Selmi C, Bowlus C, Gershwin M, et al. Primary biliary cirrhosis. Lancet. 2011;377:1600-1609 
Spiegelman D, Hertzmark  Am J Epidemiol. 2005 Aug 1;162(3):199-200. Epub 2005 Jun 29. Easy 
SAS calculations for risk or prevalence ratios and differences. 
 
 
 


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APPENDICES 
APPENDIX I: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 


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APPENDIX III: PERMITTED/NON-PERMITTED MEDICATION 
 
Table 3: Non-Permitted Medication and Condition  
Medications 
When 
Medication that may interact with absorption, metabolism, etc  
Indomethacin 
From Pre-randomization up to EOT or EOS Visit 
Same pharmacological class (PPAR agonists) 
Thiazoledinediones (glitazones) 
From 2 months prior to screening visit up to EOT 
or EOS Visit 
Fibrates 
From 2 months prior to screening visit up to EOT 
or EOS Visit 
Therapies for treatment of PBC 
Obeticholic acid 
From 2 months prior to screening visit up to EOT 
or EOS Visit 
Other Medications  
Budesonide and other systemic Corticosteroids  
From 3 months prior to screening visit up to EOT 
or EOS Visit 
Azathioprine 
Colchicine 
Cyclosporine 
Methotrexate 
Mycophenolate Mofetil 
Pentoxyfilline 
Alpha-methyl-dopa 
Sodium valproic acid 
Isoniazide 
Nitrofurantoin 
Antibodies or immunotherapy directed against interleukins or 
other cytokines or cheomkines 
From 12 months prior to screening visit up to EOT 
or EOS Visit 
 
Table 4: Permitted Medication and Condition  
Medications 
When 
Therapies for treatment of PBC 
Ursodeoxycholic acid 
Taken for at least 12 months prior to the screening visit with 
Dose stability required from at least 6 months prior to Screening  
Therapies for management of pruritus in PBC patients 
Rifamycin 
Taken for at least 6 months prior to the screening visit 
Dose stability for at least 3 months prior to the screening visit, and the 
intent of maintaining that stable dose throughout the study up to EOT or 
EOS visit.  
Lipid lowering therapy 
Statins 
Dose stability required from at least 2 months prior to Screening  
Ezetimibe 
 
 
 


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APPENDIX IV: ALCOHOL COMPARISON TABLE 
 
Alcohol type 
Alcohol by volume 
(ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units2 
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 
liquor1 
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 
Period box 
Wallet 
Protocol number 
X 
X 
X 
Sponsor details 
X 
X 
X 
Site number 
X 
 
 
Subject ID 
X 
X 
 
Kit number 
X 
X 
X 
Visit number 
- 
X 
 
Lot number 
X 
X 
X 
Expiry date 
X 
X 
X 
Contents 
X 
X 
X 
Route of administration 
X 
X 
X 
Administration instructions 
X 
X 
X 
“For Clinical Trial Use only.” 
X 
X 
X 
“Keep out of reach of Children.” 
X 
X 
X 
Storage details 
X 
X 
X 
Instructions 
for 
product 
and 
package return at next visit 
X 
X 
X 
 

SAP_001.pdf: 
Statistical Analysis Plan 
This document is proprietary and confidential to 
03.007A.03 
Page 1 of 70 
Document Type: 
Template 
Document ID: 
03.007A.03 
Issue Date:  
02 MAY 2016 
Effective Date:  
30 MAY 2016 
Sponsor Name: Genfit 
Protocol Number and Title: 
GFT505B-216-1 
A Multicenter, Double-Blind, Randomized, 
Placebo-Controlled, Phase 2 Study to Evaluate 
the Efficacy and Safety of Elafibranor at doses 
of 80 mg and 120 mg After 12 Weeks of 
Treatment in Patients With Primary Biliary 
Cholangitis and Inadequate Response to 
Ursodeoxycholic Acid 
Protocol Version and Date: 
FINAL V3.0 
04 December 2017 
<Protocol Amendment 
numbers and dates> 
 Project 
Code: 
1009105 
Author(s): 
SAP Version:  
2.0 
SAP Version Date: 
11 November 2018 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Genfit. Acceptance of 
this document constitutes agreement by the recipient that no information contained herein will 
be published or disclosed without prior written authorization from an official of Genfit. 
However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected 
breach of this obligation, 
 should be notified promptly. 
NCT03124108


Statistical Analysis Plan 
GENFIT Protocol # GFT505B-216-1 
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Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
0.2 
31-May-2017 
 
Initial Release Version 
0.3 
14-June-2017 
 
Updated Version 
0.4 
31-JUL-2018 
 
Updated Version considered final 
1.0 
01-Aug-2018 
 
Merged secondary endpoints into one table 
1.1 
05-Nov-2018 
 
Modification on statistical analyses concerning 
some laboratory parameters 
1.2 
20-Nov-2018 
 
Final modifications made after dry run and BDRM. 
Addition of one table 
2.0 
21NOV2018 
 
Clarification of EndPoint value definition 
Lysophosphatidic acid replaced by autotaxin  
Updates to be consistent throughout SAP and shells 
 
 




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Statistical Analysis Plan 
GENFIT Protocol # GFT505B-216-1 
Version 2.0 
 
 
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TABLE OF CONTENTS 
Contents 
1. GLOSSARY OF ABBREVIATIONS .............................................................. 9 
2. PURPOSE ...................................................................................... 13 
2.1. 
Responsibilities ....................................................................................... 13 
2.2. 
Timings of Analyzes .................................................................................. 13 
3. STUDY OBJECTIVES .......................................................................... 14 
3.1. 
Primary Objective .................................................................................... 14 
3.2. 
Secondary Objective(s) ............................................................................. 14 
3.3. 
Brief Description ...................................................................................... 15 
3.4. 
Subject Selection ..................................................................................... 15 
3.4.1. 
Inclusion Criteria ................................................................................ 15 
3.4.2. 
Exclusion Criteria ............................................................................... 16 
3.5. 
Determination of Sample Size ..................................................................... 19 
3.6. 
Treatment Assignment & Blinding ................................................................ 19 
3.7. 
Administration of Study Medication .............................................................. 20 
3.8. 
Study Procedures and Flowchart ................................................................. 20 
4. ENDPOINTS .................................................................................... 25 
4.1. 
Primary Efficacy Endpoint .......................................................................... 25 
4.2. 
Secondary Efficacy Endpoints ..................................................................... 25 
4.3. 
Safety Endpoints ...................................................................................... 26 
5. ANALYSIS SETS ............................................................................... 27 
5.1. 
Enrolled Set ............................................................................................ 27 


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5.2. 
Safety Set .............................................................................................. 27 
5.3. 
Intent-to-Treat ........................................................................................ 27 
5.4. 
Per Protocol Set ...................................................................................... 27 
5.5. 
Protocol Deviations .................................................................................. 27 
6. GENERAL ASPECTS FOR STATISTICAL ANALYSIS ....................................... 29 
6.1. 
General Methods ...................................................................................... 29 
6.2. 
Key Definitions ........................................................................................ 29 
6.3. 
Missing Data ............................................................................................ 31 
6.4. 
Visit Windows.......................................................................................... 31 
6.5. 
Pooling of CentREs ................................................................................... 32 
6.6. 
Subgroups .............................................................................................. 32 
7. DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION ........... 33 
7.1. 
Subject Disposition and Withdrawals ............................................................ 33 
7.2. 
Demographic and Other Baseline Characteristics ............................................. 33 
7.3. 
Medical History and Concomitant Diseases ..................................................... 34 
7.4. 
OTHER BASELINE CHARACTERISTICS .............................................................. 35 
7.5. 
Medication ............................................................................................. 35 
7.5.1. 
Prior Medication ................................................................................ 36 
7.5.2. 
Concomitant Medication ....................................................................... 36 
8. EFFICACY ...................................................................................... 38 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................... 38 
8.2. 
Secondary Efficacy Endpoints and Analyzes .................................................... 40 
8.2.1. 
Response rate based on two composite endpoints ....................................... 41 
8.2.2. 
Response rate according to PBC risk scores ................................................ 42 
8.2.3. 
Response rate according to normalized laboratory values .............................. 42 
8.2.4. 
Response rate according to reduction in ALP levels ...................................... 43 
8.2.5. 
Change from baseline .......................................................................... 43 


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9. SAFETY ........................................................................................ 46 
9.1. 
EXTENT OF EXPOSURE ............................................................................... 46 
9.2. 
Treatment Compliance .............................................................................. 46 
9.3. 
Adverse Events / Adverse Drug Reactions ...................................................... 46 
9.4. 
Laboratory Evaluations .............................................................................. 48 
9.5. 
Vital Signs .............................................................................................. 50 
9.6. 
ECG  ...................................................................................................... 51 
9.7. 
Physical Examination ................................................................................ 51 
9.8. 
StaNdard Diet and Exercise Recommendations ................................................ 51 
10. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ..................................... 52 
11. REFERENCE LIST ............................................................................. 53 
12. PROGRAMMING CONSIDERATIONS ......................................................... 54 
12.1. General Considerations ............................................................................. 54 
12.2. Table, Listing, and Figure Format ................................................................ 54 
12.2.1. 
General ........................................................................................... 54 
12.2.2. 
Headers ........................................................................................... 54 
12.2.3. 
Display Titles .................................................................................... 55 
12.2.4. 
Column Headers ................................................................................. 55 
12.2.5. 
Body of the Data Display ...................................................................... 56 
12.2.6. 
Footnotes ......................................................................................... 58 
13. QUALITY CONTROL .......................................................................... 59 
14. INDEX OF TABLES ............................................................................ 60 
15. INDEX OF FIGURES ........................................................................... 66 
16. INDEX OF LISTINGS .......................................................................... 67 
17. APPENDICES ................................................................................... 70 


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1. 
GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Description 
AASLD 
American Association for the Study of Liver Diseases 
ACR 
Albumin/Creatinine Ratio 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
ALkaline Phosphatase 
ALT 
ALanine aminoTransferase 
ANCOVA 
ANalysis of COVAriance 
AST 
Aspartate Aminotransferase 
AT 
Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BCL6 
B-Cell Lymphoma 6 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Bx 
Biological assessment visit 
C4 
serum 7α-hydroxy-4-cholesten-3-one 
CA 
Competent Authorities 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CK-18 
cytokeratin-18 
CPK 
Creatine PhosphoKinase  
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 


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CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
CYtochrome P450 
CV 
Coefficient of Variation 
DCA 
DeoxyCholic Acid 
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 
eGFR 
estimated Glomerular Filtration Rate 
EOT 
End of Study Treatment 
FDA 
Food and Drug Administration 
FGF19 
Fibroblast Growth Factor 19 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GPP 
Good Pharmacoepidemiology Practice 
HBsAg 
Hepatitis B surface Antigen 
HCC 
HepatoCellular Carcinoma  
HCV 
Hepatitis C Virus 
HDL-C 
High-Density Lipoprotein Cholesterol 
HIV 
Human Iimmunodeficiency Virus 
hPPAR 
human Peroxisome Proliferator-Activated Receptor 
HRT 
Hormonal Replacement Therapy 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IL-6 
Interleukin-6 
INR 
International Normalized Ratio 


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IP 
Investigational Product 
IR 
Insulin Resistance 
IRB 
Institutional Review Board 
ITT 
Intent-To- Treat 
IVRS/IWRS 
Integrated Voice/Web Response System 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LPLV 
Last Patient Last Visit 
LSS 
Life Science Services 
M2 
anti-inflammatory macrophages 
Max 
Maximum 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model End stage Liver Disease 
Min 
Minimum 
mITT 
modified Intent To Treat 
N/A 
Not Applicable 
NASH 
NoAalcoholic SteatoHepatitis 
NCEP ATP III 
National Cholesterol Education Program’s Adult Treatment Panel III  
NF-κB 
Nuclear Factor kappa B 
PBC 
Primary Biliary Cholangitis 
PD 
PharmacoDynamics 
PK 
PharmacoKinetics 
PPAR 
Peroxisome Proliferator-Activated Receptor 
PPS 
Per Protocol Set 
PRV 
Pre-Randomization Visit 
PT 
Preferred Term 
QC 
Quality Control 
QoL 
Quality of Life 
QTc 
corrected QT 
SADR 
Serious Adverse Drug Reaction 


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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SS 
Safety Set 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SV 
Screening Visit  
TEAE 
Treatment-Emergent Adverse Event 
TGF-β 
Transforming Growth Factor Beta 
TLC 
Therapeutic Lifestyle Change 
TLF 
Table, Listing, and Figure 
TNF 
Tumor Necrosis Factor-alpha 
UDCA 
UrsoDeoxyCholic Acid 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
UV-LLNA 
UV- Local Lymph Node Assay 
VAS 
Visual Analogue Score 
WHO 
World Health Organization 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables, and figures that will be produced and the statistical methodologies 
that will be used are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
2.1. 
RESPONSIBILITIES 
 will perform the statistical analyses and will be responsible for the 
production and quality control of all tables and listings. This SAP only describes efficacy 
and safety analyses. Pharmacokinetic (PK) analysis is not within the scope of this SAP 
and will be performed by the sponsor or sponsor-designated third party. 
2.2. 
TIMINGS OF ANALYSES 
The primary analysis of safety and efficacy is planned after all subjects complete the 
final study visit or withdraw early from the study. No interim analyses will be 
performed, and no DSMB has been set-up for this study. This SAP details these analyses 
and has been finalized prior to unblinding of the study. 
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To evaluate the efficacy of elafibranor 80 and 120 mg with respect to relative change 
from baseline in serum ALP levels compared to placebo. 
3.2. 
SECONDARY OBJECTIVE(S) 
To assess the following endpoints at Visit 5 (W+eek 12): 
 
the response to treatment based on composite endpoints: 
 
ALP < 1.67 × upper limit of normal (ULN) and total bilirubin within normal 
limit and > 15% decrease in ALP 
 
ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease 
in ALP 
 
response according to Paris I, Paris II, Toronto I, Toronto II, UK PBC risk score 
 
ALP response rates of at least 10%, 20%, and 40% decreases  
 
the response to treatment on normalization of ALP 
 
the response to treatment on normalization of bilirubin  
 
the response to treatment on normalization of albumin 
 
the change from baseline in ALT, AST, GGT, 5’nucleotidase, total bilirubin, 
conjugated bilirubin, and albumin 
 
the change from baseline in lipid parameters 
 
the change from baseline in bile acids 
 
the change from baseline in C4, FGF19 
 
the change from baseline in IgM 
 
the change from baseline in inflammatory and liver fibrosis markers 
 
the change from baseline in pruritus (through 5D-itch scale and visual analogue 
score [VAS]) 
 
the change from baseline in quality of life (using PBC 40 questionnaire) 
3.3. 
SAFETY OBJECTIVES 
To assess the tolerability and safety of once per day oral administration of elafibranor 
in 80-mg and 120-mg doses in patients with PBC: 
 
adverse events (AEs) and serious adverse events (SAEs) 
 
physical examination  
 
vital signs  
 
medical history  
 
ECG 
 
hematological parameters 
 
liver markers 
 
other biochemical safety parameters 


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3.4. 
EXPLORATORY OBJECTIVE 
To determine PK parameters of elafibranor (GFT505) 80 and 120 mg and its main active 
circulating metabolite, GFT1007, in patients with PBC and to explore an 
exposure-response relationship. PK analysis is not within the scope of this SAP and will 
be described in a separate document (see Section 2.1). 
3.5. 
BRIEF DESCRIPTION 
This is a Phase 2, proof-of-concept, randomized, double-blind, placebo-controlled trial 
to evaluate the efficacy and safety of elafibranor 80 mg and 120 mg once daily versus 
placebo in a PBC population. Patients will be randomized to 80-mg elafibranor, 120-mg 
elafibranor, or placebo in a 1:1:1 ratio.  
Patient participation will be 20 weeks maximum (including authorized margins). At the 
Screening Visit (Week -4 to Week -1), eligibility criteria will be checked. The Screening 
Visit will be followed by a pre-randomization visit, which should take place 1 week prior 
to randomization at V1 (Day 0/Week 1). Patients will then be randomized on a 1:1:1 
basis at Visit 1 (Day 0/Week 0). The patients will then attend the following visits:  
 
Visit 2 (Week 2) – Intermediate visit – 2 weeks after Day 0 
 
Visit 3 (Week 4) – Intermediate visit – 4 weeks after Day 0 
 
Visit 4 (Week 8) – Intermediate visit – 8 weeks after Day 0 
 
Visit 5 (Week 12) – Final visit – 12 weeks after Day 0 
 
End of Study (EOS) visit, for all patients who complete the double-blind 
treatment period (at least 16 days but not more than 30 days after Visit 5).  
 
End of treatment (EOT) visit in case of premature discontinuation (at least 16 
days but not more than 30 days after the final administration of study drug) 
3.6. 
SUBJECT SELECTION 
3.6.1. 
Inclusion Criteria 
1. Must have provided written informed consent 
2. Males or females 18 to 75 years of age 
3. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 
of the following 3 diagnostic factors: 
o 
History of elevated ALP levels for at least 6 months 


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o 
Positive 
Anti-Mitochondrial 
Antibodies 
(AMA) 
titers 
(> 1/40 
on 
immunofluorescence or M2 positive by enzyme-linked immunosorbent 
assay (ELISA) or positive PBC-specific antinuclear antibodies  
o 
Liver biopsy consistent with PBC 
4. ALP ≥ 1.67x upper limit of normal (ULN) (‘inadequate response to UDCA’)  
5. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to 
Screening Visit  
6. Contraception: Females participating in this study must be of non-childbearing 
potential or must be using highly efficient contraception for the full duration of 
the study and for 1 month after the end of treatment, as described below: 
a) Cessation of menses for at least 12 months due to ovarian failure 
b) Surgical sterilization such as bilateral oophorectomy, hysterectomy, or 
medically documented ovarian failure 
c) Using a highly effective non-hormonal method of contraception (bilateral 
tubal occlusion, vasectomized partner or intrauterine device) 
d) 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. 
 
7. Must agree to comply with the trial protocol 
3.6.2. 
Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
 Positive hepatitis B surface antigen (HBsAg) at Screening  
 Positive HCV RNA (tested for in case of known cured HCV infection or positive 
HCV Ab at Screening)  
 Alcoholic liver disease  
 Primary sclerosing cholangitis (PSC) 
 Definite autoimmune hepatitis (AIH) or ‘AIH-PBC overlap syndrome’  
 Biopsy-confirmed non-alcoholic steatohepatitis (NASH)  
 Known history of alpha-1 antitrypsin deficiency, or other metabolic forms of  
 chronic liver disease 
 Gilbert's syndrome (due to interpretability of bilirubin levels)  


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2. Screening CPK > ULN 
3. Screening ALT or AST > 5 ULN 
4. Screening total bilirubin > 2 ULN 
5. Screening serum creatinine > 1.5 mg/dL and eGFR < 60 mL/min/1.73 m2 
6. Significant renal disease, including nephritic syndrome, chronic kidney disease  
7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh 
B/C) 
8. Platelet count <150 X 103/mL 
9. Albumin <3.5 g/dL 
10. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including: 
 
Current Model for End-Stage Liver Disease score ≥15; current placement on a 
liver transplant waiting list, or history of undergoing liver transplantation 
 
Any record of complications of cirrhosis and/or portal hypertension such as: o 
Gastroesophageal 
variceal 
bleeding 
and endoscopic 
therapy 
and/or 
transjugular intrahepatic portosystemic shunt [TIPS] insertion  
o Ascites formation requiring intervention, eg, diuretic therapy  
o Spontaneous bacterial peritonitis  
o Hepatic encephalopathy  
o Confirmed or suspected hepatocellular carcinoma  
 
11. Hepatorenal syndrome (type I or II). Administration of the following medications 
is prohibited as specified below:  
 
From pre-randomization to EOT or V5 visit : indomethacin  
 
2 months preceding screening throughout the trial (up to last study visit): 
fibrates or obeticholic acid, thiazoledinediones (glitazones)  


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 
3 months prior to screening and throughout the trial (up to last study visit) : 
azathioprine, 
colchicine, 
cyclosporine, 
methotrexate, 
mycophenolate 
mofetil, 
pentoxifylline; 
budesonide 
and 
other 
chronic 
systemic 
corticosteroids; and potentially hepatotoxic drugs (including α-methyl-dopa, 
sodium valproic acid, isoniazide, or nitrofurantoin) 
 
12 months prior to inclusion visit and throughout the trial (up to last study 
visit): antibodies or immunotherapy directed against interleukins or other 
cytokines or chemokines  
 
NOTE: Anti-pruritus treatment, including rifamycin, is allowed if prescribed 
for at least 6 months prior to screening, patient is on stable dose at least 3 
months prior to screening, and patient continues at the same dose 
throughout the study 
12. If female: known pregnancy, has a positive urine pregnancy test (confirmed by a 
positive serum pregnancy test), or lactating 
13. Known history of human immunodeficiency virus (HIV) infection 
14. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's 
disease)  
15. Other clinically significant medical conditions that are not well controlled or for 
which medication needs are anticipated to change during the study 
16. Anticipated changes to current medications (that will be continued) during the 
course of the study 
17. History of alcohol abuse, defined as consumption of more than 30 g pure alcohol 
per day for men and more than 20 g pure alcohol per day for women, or other 
substance abuse within 1 year prior to Day 0 (randomization visit) 
18. Participation in another study with an investigational drug, biologic, or medical 
device using active substance within 30 days prior to screening, or within 5 
half-lives of the active substance, whichever is longer 
19. History of noncompliance with medical regimens or patients who are considered 
to be potentially unreliable 
20. Mental instability or incompetence, such that the validity of informed consent or 
compliance with the study protocol is uncertain 
21. Known hypersensitivity to the investigational product or any of its formulation 
excipients 


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22. Evidence of any other unstable or untreated clinically significant immunological, 
endocrine, 
hematological, 
gastrointestinal, 
neurological, 
neoplastic, 
or 
psychiatric disease 
3.7. 
DETERMINATION OF SAMPLE SIZE 
It is planned to randomize 15 patients per treatment arm (45 in total). All sample size 
calculations were done using PASS 13 software. 
Fifteen patients in each of the elafibranor arms and placebo arm or 45 patients in total 
would achieve greater than 80% power to detect a percentage decrease of 20% for each 
dose-placebo comparison. This calculation assumes that the standard deviation (on the 
percentage relative change from baseline) in each elafibranor arm is 18 and for placebo 
arm is 15 and were based on the results from the Phase 2b elafibranor trial (Clinical 
Study Report [CSR] not yet available). The sample size calculation is based on a 2-sided 
2-sample unequal-variance t-test with a significance level (alpha) of 0.05.  
3.8. 
TREATMENT ASSIGNMENT AND BLINDING 
Eligible patients will be randomized in a 1:1:1 ratio to receive elafibranor 80 mg, 
elafibranor 120 mg, or placebo using centralized randomization.  
Identification numbers will be assigned to each patient at the Screening Visit. The 
number will also be reported in the eCRF. Upon completion of the Screening Visit, if the 
patient fulfills all the criteria to enter the study, the Investigator will register the 
patient in the IVRS/IWRS (integrated voice/web response) system to pre-randomize 
him/her (at least 1 week before Visit 1).  
The IVRS/IWRS will check if the Investigator is authorized to use the system (using 
identification number and access code). The IVRS/IWRS will then allocate the patient to 
a treatment arm (placebo, elafibranor 80 mg, or elafibranor 120 mg) through a 
treatment number and will immediately forward the information to the Drug 
Distribution Centre, which will be responsible to send to the site the corresponding 
treatment package allocated to the patient for the 12-week period, within 1 week at 
most. This labeled package will include 3 period boxes, one for each period [Visit 1-Visit 
3], [Visit 3-Visit 4], and [Visit 4-Visit 5]. A confirmatory e-mail will also be sent to the 
Investigator and to the Sponsor. The pharmacy will acknowledge receipt of the study 
drug in the IVRS/IWRS.  
During the study, the Investigator, patient, and study personnel will be blinded to the 
treatment allocation. Both elafibranor and placebo tablets and packaging are 
indistinguishable. 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 IVRS/IWRS. 
The Investigator will be able to unblind any treatment carton that was dispensed to the 
patient by connecting to the IVRS/IWRS (24-hour and 7-day access) and entering 


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his/her 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 IVRS/IWRS will verify the authorization to unblind the entered treatment 
carton number, and the screen will then display the treatment arm. 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. 
3.9. 
ADMINISTRATION OF STUDY MEDICATION 
Both elafibranor and placebo tablets and packaging are indistinguishable. Patients will 
be informed to take 2 tablets per day of elafibranor 80 mg or 120 mg or placebo orally 
with a glass of water each morning before breakfast. 
The Investigator will receive one package per randomized patient, each package 
covering the full treatment period. 
Each randomized patient will be given a package at each visit from V1 to V4 (except at 
V2) containing the adequate number of tablets to cover the drug administration over 
the entire period (ie, covering at least 4 weeks of treatment + 5 days margin for each 
period): 
 
At Visit 1: the Investigator will dispense 1 labeled period box of 35 wallets of 
2 tablets  
 
At Visit 3: the Investigator will dispense 1 labeled period box of 35 wallets of 
2 tablets  
 
At Visit 4: the Investigator will dispense 1 labeled period box of 35 wallets of 
2 tablets  
 
The patient will be instructed to take the treatment orally (2 tablets per day 
before breakfast) with a glass of water 
The Investigator will confirm each study drug dispensation in the IVRS/IWRS. A specific 
IVRS/IWRS procedure manual will be provided to the Investigator. 
 
3.10. 
STUDY PROCEDURES AND FLOWCHART 
This study consists of a Screening Visit up to 4 weeks prior to randomization and 5 study 
visits over a period of 12 weeks. 


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Table 1: Study General Assessment Schedule 
 
Screening 
period 
Treatment period 
Follow-up 
period 
Visit 
SV 
V1 V1 
(PK) 
V2 
V2 
(PK) 
V3 
V4 
V5 
EOT g 
EOS 
Week 
[-4,-1] 
0 
 
2 
 
4 
8 
12 
16 to 30 days after 
last drug intake 
16 to 30 days 
after V5 
Day 
[-28, -7] 
0 
 
14 
 
28 
56 
84 
 
100-114 
Permitted Margin 
 
0 
 
14 +/- 1 
day 
 
28 +/- 2 
days 
28 +/- 2 
days 
28 +/- 2 
days 
 
16 + 14 days 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history / demographics 
X 
 
 
 
 
 
 
 
 
 
Check inclusion / exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signs & heightb & weight measurement 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
12-Lead ECG 
 
X 
 
 
 
X 
X 
X 
X 
X 
Lab evaluation (see table “study biological 
assessment schedule”) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
PK blood samplingc 
 
X 
Xd 
X 
Xd 
 
 
 
 
 
Pre-randomization 
Xe 
 
 
 
 
 
 
 
 
 
Phone call to the patient 
 
Xf 
 
X 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
IVRS/IWRS registration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review prior/concomitant/ medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus scoring (5D itch scale & VAS) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Quality of life questionnaire (PBC40) 
 
X 
 
 
 
X 
X 
X 
X 
X 
Study placebo or drug dispensation 
 
X 
 
 
 
X 
X 
 
 
 
Drug accountability and compliance 
assessment 
 
 
 
X 
 
X 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram; IVRS/IWRS = integrated voice/web response system; PK = pharmacokinetic; SV = Screening Visit; V = visit.  
a 
All inclusion/exclusion criteria, including biological and histological criteria, assessed at V1 
b 
Height is measured only at SV 
c 
There are a total of 9 PK sampling time points:  8 each at V1 and V2; the 9th sample is taken at 24 h on the following day (V1(PK) and V2(PK), respectively). 


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d 
24 h sampling time point to be done at ambulatory visit (pre-dose, fasting) 
e 
At least 1 week before visit V1 and after eligibility confirmation  
f 
A pre-randomization confirmation  
g 
only in case of premature discontinuation, EOT needs to be performed 
 
 


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Table 2: Study Biological Assessment Schedule 
 
Screening 
period 
Treatment period 
Follow-up 
period 
Visit 
SV 
SBx 
V1 
Bx1 
V2 
Bx2 
V3 
Bx3 
V4 
Bx4 
V5 
Bx5 
EOTc 
BEOT 
EOS 
Week 
[-4,-1] 
0 
2 
4 
8 
12 
16 to 30  days 
after last drug 
intake 
16 to 30 
days after V 
5 
Labs - Haematology 
haemoglobin, haematocrit, RBC, WBC, differential count, platelet count, prothrombin time, 
reticulocytes count 
X 
X 
X 
X 
X 
X 
X 
X 
Labs- Urinary Pregnancy testa 
X 
X 
 
X 
X 
X 
X 
X 
Labs – Serology 
HIV Ab I/II, HBsAg and HCV Ab (HCV RNA in case HCV Ab>0,  
X 
 
 
 
 
 
 
 
Labs – Biochemistry 
 
 
 
 
 
 
 
 
Special B1: alkaline phosphatase, ALT, AST, GGT, CPK, 5’ nucleotidase, total and 
conjugated bilirubin, albumin, creatinine, eGFR, sodium, MELD-score 
X 
 
 
 
 
 
 
 
Total: alkaline phosphatase, ALT, AST, GGT, CPK, 5 nucleotidase, total and conjugated 
bilirubin, creatinine, eGFR,  total proteins, albumin, electrolytes (sodium, potassium, 
chloride, calcium), hsCRP, fibrinogen, haptoglobin, lipase, amylase   
 
X 
X 
X 
X 
X 
X 
X 
Labs – Lipids 
 
 
 
 
 
 
 
 
Total Cholesterol, HDL-C, TG, LDL-C 
 
X 
X 
X 
X 
X 
X 
X 
Inflammatory markers 
TNF-, TGF-, IL-6, PAI-1  
 
X 
 
 
 
X 
X 
X 
Other 
IgM, urinary myoglobin b 
 
X 
 
 
 
X 
X 
X 
Liver markers: 
CK18 (M65 & M30), lysiphosphatidic acid, C4, FGF19, bile acidsd 
 
X 
 
 
 
X 
X 
X 
Labs – Urinalysis (dipstick done by central lab) 
Specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, 
leukocytes 
X 
X 
X 
X 
X 
X 
X 
X 
Safety markers 
Serum Cystatin C 
Urinary albumin, urinary creatinine, urinary ACR 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ACR = albumin/creatinine ratio; B = biological assessment visit; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 
phosphokinase; GGT = gamma-glutamyl transferase; eGFR = estimated glomerular filtration rate; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein 
cholesterol; MELD = model end stage liver disease; RBC = red blood cell; TG = triglyceride; V = visit; WBC = white blood cell.  


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a 
for Women of Childbearing potential only (WOCBP) 
 
b 
assessment of presence of myoglobin in urine may be done locally at the discretion of the PI, only in case of clinically significant CPK elevation 
c 
in case of premature discontinuation, end of treatment visit should be performed between 16 and 30 days after last drug intake 
d 
Bile acid panel includes the following:  (cholic acid (CA), glycocholic acid (GCA), taurocholic acid (TCA), chenodeoxycholic acid (CDCA), glycochenodeoxycholic acid 
(GCDCA), taurochenodeoxycholic acid (TCDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), lithocholic acid (LCA), glycolithocholic 
acid (GLCA), taurolithocholic acid (TLCA), ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid (TUDCA), hyocholic acid (HCA), 
glycohyocholic acid (GHCA), taurohyocholic acid (THCA), hyodeoxycholic acid (HDCA), glycohyodeoxycholic acid (GHDCA) and taurohyodeoxycholic acid (THDCA). 
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
The primary endpoint of the study is relative change from baseline in serum ALP levels 
comparing each elafibranor dose group to placebo at EndPoint (Visit 5 or EOT value, 
must be last post baseline value under treatment).  
All blood samples for efficacy and/or for safety assessment (as described in Table 2: 
Study Biological Assessment Schedulewill be returned and analyzed by the central 
laboratory (BARC: Ghent – Belgium, or New York – USA). 
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 on 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 CPK, 
and HCV RNA (in case of positive HCV Ab at Screening Visit). 
The laboratory value used for calculation will be the first value (and not the retest 
value) in order to reduce the delay between last study drug intake and specimen date 
collection. 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The following secondary endpoints will be assessed at EndPoint (Visit 5 or EOT value, 
must be last post baseline value under treatment): 
 
Absolute change from baseline in ALP 
 
Response to treatment based on composite endpoints: 
o ALP < 1.67 × ULN and total bilirubin within normal limit and > 15% 
decrease in ALP 


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o ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease 
in ALP 
 
Response according to Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score 
 
Response to treatment on normalization of ALP 
 
Response to treatment on normalization of bilirubin 
 
Response to treatment on normalization of albumin 
 
Response on at least 10%, 20%, 40% decrease in ALP  
 
Absolute and relative change from baseline in ALT, AST, GGT, 5’nucleotidase, total 
bilirubin, conjugated bilirubin, albumin 
 
Absolute and relative change from baseline in lipid parameters 
 
Absolute and relative change from baseline in bile acids 
 
Absolute and relative change from baseline in C4, FGF19 
 
Absolute and relative change from baseline in IgM 
 
Absolute and relative change from baseline in inflammatory and liver fibrosis 
markers 
 
Absolute and relative change from baseline in pruritus (through 5D-itch scale & 
visual analogue score VAS) 
 
Absolute and relative change from baseline in quality of life (using PBC 40 
questionnaire) 
 
Adverse Events (AEs) 
 
Cardiovascular parameters (12-lead ECG, heart rate, blood pressure) 
 
Hematology and safety parameters 
4.3. 
SAFETY ENDPOINTS  
The tolerability and safety of once per day oral administration of elafibranor in 80-mg 
and 120-mg doses in patients with PBC: 
 
adverse events (AEs) and serious adverse events (SAEs) 
 
physical examination  
 
vital signs  
 
medical history 
 
ECG 
 
hematological parameters 
 
liver markers 
 
other biochemical safety parameters 


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5. 
ANALYSIS SETS 
5.1. 
ENROLLED SET 
The Enrolled Set will include all subjects who sign informed consent. This set will be 
used for subject listings and summaries of subject disposition. 
5.2. 
SAFETY SET  
The Safety Set (SS) will include all randomized subjects who were administered at least 
one dose of study medication. Subjects will be analyzed according to treatment 
received. The SS will be used for all analyses of safety. 
5.3. 
     INTENT-TO-TREAT 
The Intent-to-Treat (ITT) population will include all randomized subjects.  
Based on the ITT principle, the modified ITT (mITT) will include all randomized patients 
receiving at least one study drug dose with available baseline value and at least one 
post baseline value for the primary endpoint Subjects will be analyzed according to 
randomized treatment. The mITT population will be used for all analyses of primary and 
secondary efficacy endpoints. 
5.4. 
PER-PROTOCOL SET  
The per-protocol Set (PPS) includes all subjects from the mITT population who are 
compliant with the study protocol without any major protocol deviations. Classification 
of protocol deviations as major or minor will be agreed on at the Data Review Meeting 
(DRM) prior to database lock. Analysis based on the PPS will be performed for the 
primary efficacy endpoint and key secondary endpoints as an additional analysis. 
Subjects will be analyzed according to randomized treatment. 
Criteria for exclusion from the PPS are defined in section 5.5. 
5.5. 
PROTOCOL DEVIATIONS 
Protocol deviations are collected and agreed at the DRM to evaluate protocol deviations 
considered to have major impact on subject safety or the validity of the study data. 
Subjects with major protocol deviations will be excluded from the PPS under the 
assumption that the deviation may have an impact on the efficacy analysis. Important 
protocol deviation categories may include, but are not limited to the following: 
 
Inclusion/Exclusion Criteria not met 
 
Informed Consent: Informed Consent Form not signed or signed late 


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 
Informed Consent: Other 
 
Randomization: Randomized and Not Treated 
 
Randomization: Treated and not randomized 
 
Randomization: Multiple Randomizations 
 
Randomization: Other 
 
Investigation Product/Dosing: Incorrect IP kit given to Patient 
 
Investigation Product/Dosing: IP Storage 
 
Investigation Product/Dosing: IP Dosing 
 
Investigation Product/Dosing: other 
 
Prohibited Concomitant Treatment 
 
Visit Window 
 
Study Procedure: Major Non-Compliance  
 
Site Staff Authorization, Delegation, Training 
Further major protocol deviations will be defined during the DRM.  


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
All subjects entered into the database will be included in subject data listings. Summary 
tables will be provided for all subjects. Unless otherwise specified, all demographic and 
baseline data will be presented by treatment arm and overall. Efficacy and safety data 
will be presented by treatment arm.   
Quantitative (continuous) data—absolute values and changes from baseline, where 
appropriate—will be summarized with number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Confidence intervals (CIs; 95%, 
2-sided) will be added where applicable.  
In the case of similarity between the ITT and mITT, the primary population for efficacy 
analysis will be the ITT set and otherwise the mITT set. Supportive analyses based on 
the PPS will be conducted for the primary and key secondary endpoints. The primary 
population for safety analysis will be the safety population. 
Qualitative (categorical) data will be summarized using number of observations (n) and 
frequency and percentages of subjects. Unless stated otherwise, the calculation of 
percentages will be based on the total number of subjects with nonmissing data in the 
set of interest. Confidence intervals (CIs; 95%, 2-sided) will be added, where applicable. 
The laboratory value used for calculation of primary and secondary biological endpoints 
will be the first value (and not the retest value) in order to reduce the delay between 
last study drug intake and specimen date collection. 
All tests of hypotheses will be 2-sided and conducted at the 5% significance level, and 
all confidence intervals (CIs) will be 2-sided at the 95% level. No adjustment for 
multiplicity will be made for the primary and secondary efficacy variables.   
All statistical analyses will be performed using SAS® (Version 9.3 or higher, SAS Institute 
Inc., Cary, NC, USA). 
6.2. 
KEY DEFINITIONS 
Definition of Baseline 
Baseline value is defined as last nonmissing value prior to first study drug dose. 
For all secondary and safety endpoints, the same definition will apply. It will be 
assumed that all assessments on Day 0 occur prior to dosing. 
 


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End of Treatment (EOT) Visit 
In case of premature discontinuation of the study drug, EOT visit refers to the visit 
scheduled within 30 days of final study drug administration. 
End of Treatment (EOT) Value 
Last post-baseline value under treatment. 
End of Study (EOS) Visit 
For all patients who complete the double-blind treatment period, the EOS visit refers to 
the visit scheduled at least 16 days but not more than 30 days after Visit 5. 
Treatment Period 
The Treatment Period covers the duration that a subject is under treatment in the study 
between the date of first study drug intake and the date of last study drug intake. 
Study Duration (in days)  
Day of study termination = Date of EOS visit  (or EOT visit in case of premature 
discontinuation) – Date of Visit 1(Day 0) + 1  
Definition of Study Completion and Withdrawal 
A subject will be defined as “study completed” if s/he completes the follow-up period 
of the study after having performed all the planned visits. Termination/withdrawal at a 
different time point will be considered as study discontinuation/withdrawal. 
Endpoint Value 
Endpoint value is considered the value at Visit 5 (Week 12) or EOT value (last post-
baseline value under treatment). 
Relative Change from Baseline  
Relative change from baseline is defined as percentage change from baseline to 
Endpoint. 
Change from Baseline 
Absolute change from baseline: 
Absolute change = Post baseline value – Value at baseline 


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6.3. 
MISSING DATA 
The primary efficacy endpoint is based on the availability of a post baseline measure of 
ALP. 
Incomplete/missing start and stop dates will be handled as follows:  
Incomplete AE/concomitant medication or treatment start date will be imputed:  
If the AE/concomitant medication or treatment start month = month of the first 
treatment, the missing start day will be imputed with the day of the first treatment, 
otherwise Missing start day with ‘01’. 
If the AE/concomitant medication or treatment start year = year of the first treatment 
then with the date of the first treatment. Missing start year with the date of the first 
treatment, 
otherwise Missing start day and month with the 1st of January. 
Incomplete AE/concomitant medication or treatment stop date will be imputed:  
Missing stop day with last day (28/29/30/31) of the month.  
Missing stop day and month with 31st of December.  
Missing stop year with the date of study termination. 
For all other data, all available data will be included in the analyses and will be 
summarized as far as possible. Unless otherwise specified, there will be no substitution 
of missing data, ie, missing data will not be replaced; missing data will be handled as 
‘missing’ in the statistical evaluation. 
6.4. 
VISIT WINDOWS 
The following visit windows are currently proposed for this study. These are protocol 
defined windows but visits will be included in the TLFs as recorded in the CRF. 
 


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Table 3: Visit Windows 
Visit 
Target Trial Day 
Allowable window 
Screening (Week -4 to -1) 
-28 to -7 
N/A 
Visit 1 (randomization/ Week 0) 
0 
0 
Visit 2 (Week 2) 
14 
± 1 day 
Visit 3 (Week 4) 
28 
± 2 days 
Visit 4 (Week 8) 
56 
± 2 days 
Visit 5 (Week 12) 
84 
± 2 days 
EOT* 
Within 16-30 days 
post last drug intake 
N/A 
EOS** 
Within 16-30 days 
post V5 
N/A 
* 
Only in case of premature discontinuation 
** Only in case of patients completing V5 
 
6.5. 
POOLING OF CENTERS 
No investigation of center effects is planned; data from all centers will be pooled. 
6.6. 
SUBGROUPS 
No subgroup analyses are planned for this study. 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
In the case of similarity between the SS, ITT and mITT and consistency between actual 
and assigned treatments, tables will not be duplicated. 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be summarized by presenting the number of subjects enrolled in 
the study (signed informed consent) and the number and percentage of patients that 
were: 
 
Screen Failures (Enrolled Population) 
 
Randomized (Enrolled Population) 
 
Received at least 1 dose of study medication (Enrolled population) 
 
Number of subjects in each analysis set (SS, ITT, mITT, PPS) 
 
Completed the 12-week treatment period 
 
Discontinued from the study with primary reason for premature discontinuation 
The summaries will be presented by treatment arm (elafibranor 80 mg, elafibranor 
120 mg, and placebo) and overall.  
Listings including the patient disposition, status with respect to inclusion and exclusion 
criteria, and population eligibility will be presented.  
Major protocol deviations and deviations that may affect the efficacy analysis will be 
summarized for randomized subjects by treatment arm (elafibranor 80 mg, elafibranor 
120 mg, and placebo) and overall. All protocol deviations will be listed, and sorted by 
patient number and date of deviation (if available). This by-patient listing will identify 
whether a specific protocol deviation is major or minor, and whether it is considered to 
potentially affect the analysis of efficacy. 
All data will be listed and sorted by patient number. 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics will be based on the information provided at the Screening 
Visit. The characteristics will be presented by treatment schedule (elafibranor 80 mg, 
elafibranor 120 mg, and placebo) and overall for each analysis set (SS, ITT, mITT, and 
PPS). The characteristics to be summarized are given below with details of whether 
they will be summarized as categorical or continuous:  


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 
Age (years)-continuous 
 
Gender-categorical  
 
Race-categorical  
 
Ethnicity-categorical 
 
Height (cm)-continuous  
 
Weight (kg) -continuous  
 
BMI (kg/m2)- continuous 
 
SBP (mgHg) 
 
DBP (mgHg) 
 
Pulse Rate (Beats/min) 
 
Childbearing potential status-categorical  
 
Screening Visit and Baseline Biological labs  (including haematology, 
Biochemistry, Lipids, Inflammatory Markers, Liver Markers...-Continuous 
Age at study entry will be calculated as (date the informed consent was signed – date of 
birth) / 365.25 rounded down to the nearest integer. 
All data will be listed. 
Viral serology data (HIV, hepatitis B, and hepatitis C) assessed at screening will be listed 
only.  
7.3. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
The medical history reported on the eCRF will be coded to Medical Dictionary for 
Regulatory Activities (MedDRA) terminology (latest available version). 
Medical history will be defined as any clinically significant past medical conditions that 
ended before screening. Medical history will be summarized for the SS population with 
number and percentage of subjects with at least one medical history item, and number 
and percentage of subjects by system organ class (SOC) and preferred term (PT). The 
terms will be sorted alphabetically by SOC and PT. 
Concomitant diseases will be defined as any clinically significant current medical 
conditions that were ongoing at screening. Concomitant diseases will be summarized for 


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the SS, ITT and mITT sets with number and percentage of subjects with at least one 
concomitant disease, and number and percentage of subjects by system organ class 
(SOC) and preferred term (PT). The terms will be sorted alphabetically by SOC and PT. 
Concomitant diseases will be flagged on the medical history data listing. 
7.4. 
OTHER BASELINE CHARACTERISTICS 
Baseline characteristics are defined as all results of the examinations performed prior 
to the first elafibranor or placebo administration at the randomization visit. These 
include several safety laboratory tests that will be summarized by treatment arm and 
overall by means of summary statistics (see Section 9 for more details). 
Baseline characteristics for screened failed subjects will be provided. 
Administration of standard diet and exercise recommendations at Screening Visit will be 
listed only. 
7.5. 
MEDICATION 
Prior and concomitant medications (during and after treatment) will be coded using the 
latest available version of the Anatomical-Therapeutic-Chemical (ATC) classification 
text from the World Health Organization Drug Dictionary (WHO DD) and summarized 
separately. The number and percentage of patients taking a medication will be 
displayed by therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
generic term. If a therapeutic subgroup or preferred term is unavailable ‘Uncoded’ will 
be used. Patients will only be counted one time in each unique ATC-Level 2, ATC-Level 
4 and generic term. Tables will be sorted alphabetically by therapeutic subgroup and 
preferred drug name.  
If it is identified after Randomization that any nonpermitted drugs have been 
administered to a patient within the excluded timeframes, the patient will be 
permanently discontinued from the study drug. The number and percentage of subjects 
taking nonpermitted medication or treatment during the study will be summarized 
within the protocol deviation summary. Prohibited medications and timeframe for 
exclusion are listed in Table 4.  
All prior and concomitant medications will be listed and will include both the 
medication name as reported by the Investigator as well as the coded information.    


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Table 4: Nonpermitted Medications 
Medication 
Time window for exclusion 
Indomethacin 
From Randomization up to EOT Visit 
Thiazoledinediones (glitazones) 
From 2 months prior to Screening Visit up to EOT Visit 
Fibrates 
From 2 months prior to Screening Visit up to EOT Visit 
Obeticholic acid 
From 2 months prior to Screening Visit up to EOT Visit 
Budesonide and other systemic corticosteroids  
From 3 months prior to Screening Visit up to EOT Visit 
Azathioprine 
From 3 months prior to Screening Visit up to EOT Visit 
Colchicine 
From 3 months prior to Screening Visit up to EOT Visit 
Cyclosporine 
From 3 months prior to Screening Visit up to EOT Visit 
Methotrexate 
From 3 months prior to Screening Visit up to EOT Visit 
Mycophenolate 
From 3 months prior to Screening Visit up to EOT Visit 
Mofetil 
From 3 months prior to Screening Visit up to EOT Visit 
Pentoxyfilline 
From 3 months prior to Screening Visit up to EOT Visit 
Alpha-methyl-dopa 
From 3 months prior to Screening Visit up to EOT Visit 
Sodium valproic acid 
From 3 months prior to Screening Visit up to EOT Visit 
Isoniazide 
From 3 months prior to Screening Visit up to EOT Visit 
Nitrofurantoin 
From 3 months prior to Screening Visit up to EOT Visit 
Antibodies or immunotherapy directed against 
interleukins or other cytokines or cheomkines 
From 12 months prior to Screening Visit up to EOT Visit 
 
7.5.1. 
Prior Medication 
Prior medications are defined as medications taken at any time during the 30 days prior 
to screening that stop before the administration of the first dose of study drug at 
randomization visit (Day 0). Any changes to prior medications (dose, regimen, etc.) 
during the study will be considered a new Concomitant Medication.   
The number and percentage of subjects with prior medications will be summarized for 
the SS by therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and generic 
term. 
In addition, prior Duration (years) and Dose (mg) at screening of UDCA will be 
summarized separately. 
Prior duration of UDCA at screening will be calculated as [(date of screening – date of 
first UDCA dose)+1]/ 365.25 rounded to one decimal precision.   
 
7.5.2. 
Concomitant Medication 
Concomitant medications are those with a start date on or after the first dose of study 
treatment, or those with a start date before the first dose of study treatment and a 
stop date on or after the first dose of study treatment or still ongoing at the end of the 
study. 


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If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
The number and percentage of subjects with concomitant medications during the 
treatment phase will be summarized for the SS by therapeutic class (ATC-Level 2), 
chemical subgroup (ATC-Level 4), and generic term. 


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8. 
EFFICACY 
In the case of similarity between the ITT and mITT, all efficacy analyses will be 
conducted on the ITT set and otherwise on the mITT set. Supportive analysis of the 
primary efficacy endpoint and key secondary endpoints will be conducted using the PPS. 
In addition to the statistical analyses described in the sections below, descriptive 
summaries (as per Section 8) and data listings sorted by unique patient number will be 
presented for all efficacy variables. 
All blood sampling for primary and secondary efficacy endpoints will be performed by 
trained personnel at each site. Blood samples will be processed and shipped as outlined 
in the laboratory manual.  
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy endpoint is defined as relative change from baseline to Endpoint in 
serum ALP.   
Actual values and the relative change from baseline will be summarized with descriptive 
statistics for continuous variables. 
Relative change in ALP will be calculated by: 
[(Endpoint value – Baseline Value) / Baseline value)] x 100.  
Baseline value will be computed as last nonmissing value prior to first study dose at 
randomization visit (V1). 
Endpoint will be computed as: 
 
Value at V5 or 
 
EOT value (must be last postbaseline value under treatment). 
ALP relative change from baseline will be summarized as continuous by treatment arm.  
The relative change in ALP from baseline will be compared between 120 mg elafibranor 
and placebo and between 80 mg elafibranor and placebo using a nonparametric 
randomization-based Analysis of Covariance method (LaVange et al, 2005). This 
methodology uses weighted least squares on the treatment differences of outcome and 
covariate means. The resulting model estimates give the treatment effects for the 
outcomes, adjusting for the covariates added into the model. 
The method will be applied using the SAS NParCov4 macro (©Zinc and Koch, 2001), 
adjusting for baseline ALP level as a covariate. It is important to note that this method 


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can only be applied to data with a binary treatment variable. Each dose-placebo 
comparison will be performed independently, not accounting for multiplicity. 
The macro will be applied to compare the relative change from baseline in ALP 
(PCTCHG) between the 2 active treatments (elafibranor 80 mg, 120 mg) and placebo, 
adjusting for baseline ALP (BASE). If there are baseline imbalances that are deemed to 
be important in influencing the relative change of ALP due to random chance, the 
corresponding variables may be added as further explanatory variables in the primary 
and supportive models. 
Assumptions for this model are minimal: 
 
Randomization to treatment  
 
Subjects in the trial are a simple random sample  
The macro will be applied in the following steps: 
1. Create a dataset DATAIN. The dataset should include one observation per subject and 
include the variables TRTPN (1 denotes placebo, 2 denotes elafibranor 80mg and 3 
denotes elafibranor 120mg), BASE (baseline ALP) and PCTCHG (relative change at 
endpoint in ALP from baseline) calculated as described above. Restrict DATAIN to 
subjects with TRTPN=1 and TRTPN=2.  
2. Apply the macro as shown: 
%NPARCOV4(OUTCOMES=PCTCHG,COVARS=BASE,C=0,HYPOTH=NULL,STRATA=NONE,TRTG
RPS=TRTP, TRANSFORM=NONE,COMBINE=NONE,DSNIN=DATAIN,DSNOUT=DATAOUT) 
3. Dataset _OUTDAT_COVTEST contains the evaluation of the covariate imbalance. P-
value > 0.05 indicates random imbalance for the distribution of covariates between the 
2 treatments.  
4. Extract the relevant data from the output datasets. Dataset _OUTDAT_DEPTEST gives 
the estimate (beta), standard error (sebeta) and p-value (pvalue) for the treatment 
difference and dataset _OUTDAT_CI gives a 95% CI for this treatment estimate. The 
model compares TRTPN 2 vs 1.  
5. Repeat steps 1-4 for elafibranor 120 mg vs. placebo (TRTPN = 1 and TRTPN=3). 
A supportive analysis of elafibranor’s effect on ALP changes will be conducted based on 
an analysis of covariance (ANCOVA) model, with relative change in ALP from baseline as 
the response variable and with the treatment arm and baseline ALP level as explanatory 
variables.  
This will be applied in the following steps: 


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1. Take the full dataset DATAIN, described above with all 3 treatment arms retained in 
the dataset. 
2. In order to assess the equality of slopes assumption, the model is run including the 
interaction effect between TRTPN and BASE. 
PROC GLM DATA=DATAIN; 
 
CLASS TRTPN (ref=’1’); 
 
model PCTCHG=TRTPN BASE TRTPN|BASE/solution; 
           lsmeans TRTPN/CL PDIFF ; 
run; 
If p-value for interaction is <0.05, equal slopes cannot be assumed and we cannot run 
the model without the interaction effect. A significant interaction indicates that the 
covariate influences the response variable and that it needs to be taken into account.   
If p-value for the interaction is >0.05 then the equality of slopes assumption is met and 
the model is assessed by: 
PROC GLM DATA=DATAIN; 
 
CLASS TRTPN (ref=’1’); 
 
model PCTCHG=TRTPN BASE /solution; 
 
lsmeans TRTPN/CL PDIFF ; 
run; 
If there are baseline imbalances, determined above, that are deemed to be clinically 
important in influencing the relative change of ALP due to random chance, the 
corresponding variables may be added as further explanatory variables in the supportive 
model as in the primary model. The SAS code above will be repeated, including these 
covariates. 
 
8.2. 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
All secondary endpoints will be calculated at EndPoint (Visit 5 (Week 12) or EOT value, 
must be last post baseline value under treatment. 
For all secondary endpoints involving binary outcomes (response to composite 
endpoints, response rate according to PBC risk scores, normalization of bilirubin and 
albumin), the differences in proportions will be assessed independently for each dose-
placebo comparison using the Fisher exact test. Number of responders for each 
endpoint will summarized with descriptive statistics for categorical variables. These 
outcomes are detailed in 8.2.1 to 8.2.4 below. 
For calculation of response, the following ULN and reference ranges will be used: 


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 
ALP ULN 105 U/L for females, 129 U/L for males 
 
BIL ULN <1.20 mg/dL 
 
ALB reference range: 3.5-5.2 g/dL for patients aged 18y-60y. 3.2-4.6 g/dL for 
patients aged 61y-91y  
 
ALT ULN<33 U/L for females, <41 U/L for Males 
 
PLT reference range: 170-390 for females, 165-310 for males. 
Example SAS code is shown below for the first dose-placebo comparison where DATAIN 
is the dataset defined above with one row per subject including the response and 
treatment variables: 
PROC FREQ DATA=DATAIN; 
where TRTPN = 1 and TRTPN = 2; 
TABLES RESPONSE*TRTPN/FISHER; 
run; 
If important baseline imbalances occur by chance, determined above, confounding 
variables may be added into a binomial regression model. 
Continuous secondary endpoints will be summarized with descriptive statistics for 
continuous variables. These outcomes are detailed in 8.2.2 for PBC risk score 
(calculated based on the UK-PBC score) and in 8.2.5 below.  
For all secondary endpoints involving continuous outcomes, the differences in each 
dose-placebo comparison will be assessed: 
- For relative change from baseline, using a nonparametric randomization-based 
Analysis of Covariance method similar to that used as the primary efficacy analysis 
for the primary efficacy endpoint (see section 8.1). 
- For absolute change from baseline, using an ANCOVA model, similar to that used 
as the supportive analysis for the primary efficacy endpoint (see section 8.1). 
 
Certain endpoints such as absolute and relative change from baseline in QOL (PBC40), 
Pruritus scoring (5D itch scale) and VAS will be summarized descriptively only.  
8.2.1. 
Response Rate Based on 2 Composite Endpoints 
Response will be defined using 2 separate composite endpoints: 


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 
ALP less than 1.67 X ULN and total bilirubin within normal limit and >15% 
reduction in ALP from baseline 
 
ALP < 2 × ULN and total bilirubin within normal limit and > 40% reduction in ALP 
from baseline 
8.2.2. 
Response Rate according to PBC Risk Scores 
Response rates will be defined according to each following definition: 
 
Paris I: ALP ≤3x ULN, AST ≤2x ULN and normal bilirubin  
 
Paris II: ALP and AST ≤1.5x ULN with normal bilirubin  
 
Toronto I: ALP ≤1.67x ULN  
 
Toronto II: ALP ≤1.76   
In addition, continuous PBC risk score will be calculated at EndPoint (Visit 5 or EOT 
value) based on the UK-PBC score. This will be calculated at each of the 3 survivor 
functions, detailed below.  
UK-PBC: 1-baseline survival function^exp(0.0287854*(alpEPxuln-1.722136304) - 
0.0422873*(((altastEPxuln/10)^-1) - 8.675729006) + 1.4199 * (LN(bilEPxuln 
/10)+2.709607778) -1.960303*(albxlln -1.17673001)-0.4161954*( pltxlln -
1.873564875)) 
Where: 
Baseline survivor function=0. 982 (at 5 years); 0. 941 (at 10 years); 0.893 (at 15 
years). 
alpEPxuln=ALP at EndPoint/Upper Level Normal ALP  
altastEPxuln=(ALT, AST or TA) at EndPoint/upper level normal of the value 
bilEPxuln=bilirubin at EndPoint/upper level normal bilirubin 
albxlln=alb at baseline/alb lower level normal 
pltxlln=plt at baseline/ plt lower level normal 
Only descriptive statistics at EndPoint will be provided on the continuous PBC risk score.  
8.2.3. 
Response Rate According to Normalized Laboratory Values 
Response defined as percent of patients with a normalized level of each of the following 
laboratory parameters and endpoint: 
 
ALP 
 
ALB 


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 
BIL 
8.2.4. 
Response Rate According to Reduction in ALP Levels 
Response is calculated by a reduction in ALP from baseline of at least: 
 
10% 
 
20% 
 
40% 
8.2.5. 
Change from Baseline 
All laboratory parameters will be analyzed using international units.   
Absolute and relative change at EndPoint (Visit 5/ EOT value) from baseline will be 
calculated for the following parameters: 
 
gamma-glutamyl transferase (GGT)  
 
alanine aminotransferase (ALT)  
 
aspartate aminotransferase (AST)  
 
5’nucleotidase 
 
bilirubin (total and conjugated)  
 
albumin  
 
total cholesterol, LDL-chol, HDL-Chol, Triglycerides 
 
Bile acids : Total Free, Total Conjugated and Total where: 
o Total Free = sum(CA, CDCA, DCA, LCA, UDCA, HCA, HDCA)  
o Total conjugated = sum(GCA, GCDCA, GDCA, GLCA, GUDCA, GHCA, 
GHDCA, TCA, TCDCA, TDCA, TLCA, TUDCA, THCA, THDCA)  
o Total = sum(Total free, Total conjugated) 
 
C4, FG19 
 
IgM  


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 
Biomarkers of inflammation and liver fibrosis: TNF-α, TGF-β, IL-6, 
cytokeratin-18 (CK-18), and autotaxin 
 
Quality of life: PBC 40 QOL-Descriptive Only 
 
Pruritus: 5-D Pruritus Questionnaire and Visual Analogue Score (VAS)-Descriptive 
Only 
The PBC40 QOL questionnaire is scored by domain by summing all of the values from 
the corresponding question. Values are assigned to the response in each question as 
detailed below: 
Domain/ Question Number 
Response/ Score 
Digestion and Diet 
Total Score=15 
1 
Never=5, Rarely=4, Sometimes=3, Most of the time=2, 
Always=1 
2 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5 
3 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5, Did not apply=0 
Experience any of the Following 
Total Score=20 
4-7 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5 
Itching 
Total Score=15 
8-10 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5, Did not apply=0 
Fatigue 
Total Score=40 
11-18 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5 
Effort and Planning 
Total Score=15 
19-21 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5 
Memory and Concentration 
Total Score=30 
22-27 
Never=1, Rarely=2, Sometimes=3, Most of the time=4, 
Always=5 
Affects you as a person 
Total Score=30 
28,30, 32-33 
Not at all=1, A little=2, Somewhat=3, Quite a bit=4, Very 
Much=5 
29,31 
Not at all=1, A little=2, Somewhat=3, Quite a bit=4, Very 
Much=5, Does not apply=0 
Effects your social life 
Total Score=20 
34-37 
Strongly Agree=5, Agree=4, Neither Agree nor Disagree=3, 
Disagree=2, Strongly Disagree=1 
Overall Impact on your life 
Total Score=15 
38-39 
Strongly Agree=5, Agree=4, Neither Agree nor Disagree=3, 
Disagree=2, Strongly Disagree=1 
40 
Strongly Agree=1, Agree=2, Neither Agree nor Disagree=3, 
Disagree=4, Strongly Disagree=5 


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The total Pruritus scoring (5D itch scale) score is generated by summing across all 
questions.  
 
 


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9. 
SAFETY 
All analyses described in this section will be performed on the SS and will be presented 
by treatment arm. The results will be descriptive in nature. All data will be summarized 
and listed.  
Safety will be assessed on the basis of exposure, compliance, AEs, laboratory 
parameters, vital signs and physical examination. 
9.1. 
EXTENT OF EXPOSURE 
The duration of exposure will be expressed as the time in days from the first treatment 
through to last treatment day (inclusive). Duration of exposure will be summarized for 
the SS using summary statistics for continuous variables. 
9.2. 
TREATMENT COMPLIANCE  
From Visit 1 and at subsequent visits while the patient is being treated with the study 
drug, the patient will be directed to bring back all used and unused cartons and 
blisters. Compliance will be checked with the Investigator during those visits and 
recorded on the electronic case report form (eCRF). The total number of days 
treatment was interrupted during the treatment period will be summarized using 
summary statistics for continuous variables for estimation of drug compliance, 
treatment interruptions will be recorded on the eCRF and percentage compliance will 
be calculated as: 100 * actual tablets taken/expected tablets taken where tablets 
actual taken is defined as the sum of the tablets taken and tablets expected to be taken 
is defined as (date of last dose – date of first dose) + 1.  
 The number and percentage of compliant patients will be presented for the SS, where 
compliant is defined as percentage compliance between 80.0% and 120.0% inclusive. 
The following percentage compliance categories will be presented :<80.0%; ≥80.0% to 
<120.0%; ≥120.0% 
9.3. 
ADVERSE EVENTS / ADVERSE DRUG REACTIONS 
Adverse events (AEs) will be coded using MedDRA to give a preferred term and a SOC 
term for each event.  
All reported AEs (whether treatment emergent or not) will be included in by-subject AE 
listings. A separate listing will be created with all the distinct levels of SOC, Preferred 
Terms and the verbatim Investigator description reported in the study. Sorting will be 
alphabetically by SOC, Preferred Term and then verbatim description. 
An AE is defined as 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. The term 


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AE is synonymous with the term “adverse experience” as used by the Food and Drug 
Administration (FDA). 
 
treatment emergent AE (TAEs) are events with start date on or after the date 
of first dose of study treatment and up to 28 days after date of last dose of 
study treatment or events with start date prior to the date of first dose of 
study treatment whose severity worsens on or after the date of first dose of 
study treatment. A SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect (including fetal malformations associated 
with spontaneous abortions or elective abortions) 
 
Is another medically important condition 
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 (eg, laboratory testing 
procedure, liver biopsy) must be reported as an SAE. 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is 
noxious and unintended and that is considered causally related to an investigational 
medicinal product. A serious ADR (SADR) is an ADR which meets the seriousness criteria. 
Summary tables will be based on treatment-emergent adverse events (TEAEs). 
Relationship to study drug is categorized as “related”, “possibly related”, “unlikely 
related”, “not related” and “not assessable. Relationship to trial medication is not 
expected to be missing after data cleaning, however, if relationship is confirmed as 
missing, the AE will be considered as treatment related. 
The incidence of TEAEs will be presented using counts and percentages of patients with 
AEs and tabulated by SOC and PT. SOC will be sorted alphabetically and PT within SOC 
will be sorted by descending frequency based on the incidence across subjects overall. 
If a patient has multiple occurrences (start and stop) of an event associated with a 
specific SOC or PT within a SOC, a patient will only be counted once in the incidence 
count for the SOC or PT within SOC respectively. 
The incidence of all AEs by SOC and PT will be presented for the following categories: 


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 
Any AE 
 
Any TEAEs 
 
Any TEAEs related to study medication 
 
Any Serious TEAEs 
 
Related Serious TEAEs 
 
Any TEAEs leading to permanent withdrawal of study drug 
 
Any TEAEs by maximum intensity 
Deaths, other SAEs, and AEs leading to permanent or temporary withdrawal of study 
drug will be listed including the treatment arm, start and stop dates/times of the AE, 
and days on study relative to the day of first dose of study drug.   
The following listings will be provided: 
 
Listing of subjects who died 
 
Listing of subjects with Serious TEAEs 
 
Listing of subjects with non-treatment-emergent SAEs 
 
Listing of subjects with TEAEs leading to withdrawal or temporary withdrawal of 
study drug 
9.4. 
LABORATORY EVALUATIONS 
All laboratory analyses will be analyzed by the central laboratory (BARC: Ghent – 
Belgium, or New York – USA).  
As a general rule of thumb, each value below/above the limit of quantification will be 
imputed numerically to the nearest value below/above the limit, respecting the same 
number of digits than numerical values (e.g. if the number of digit=0, substract/add 1 
to the limit of quantification; if the number of digit=1, substract/add 0.1 to the LOQ, 
etc). 
Clinical laboratory evaluations include hematology, chemistry and urinalysis. The 
parameters to be assessed along with the time-points for measurement are given in 
Table 5 below. 


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Table 5: Clinical laboratory parameters  
For each parameter not marked with an asterisk in the above table, laboratory tests and 
change from baseline will be summarized by treatment arm at each scheduled visit 
Laboratory Parameter 
Time Points Assessed 
Hematology 
haemoglobin 
V1 to V5 or EOT value 
haematocrit 
V1 to V5 or EOT value 
RBC 
V1 to V5 or EOT value 
WBC 
V1 to V5 or EOT value 
differential count 
V1 to V5 or EOT value 
platelet count 
V1 to V5 or EOT value 
prothrombin time 
V1 to V5 or EOT value 
reticulocytes count 
V1 to V5 or EOT value 
Biochemistry 
alkaline phosphatase  
V1 to V5 or EOT value 
ALT  
V1 to V5 or EOT value 
AST  
V1 to V5 or EOT value 
GGT 
V1 to V5 or EOT value 
CPK 
V1 to V5 or EOT value 
5 nucleotidase 
V1 to V5 or EOT value 
total and conjugated bilirubin 
V1 to V5 or EOT value 
creatinine 
V1 to V5 or EOT value 
eGFR* 
V1 to V5 or EOT value 
total proteins 
V1 to V5 or EOT value 
albumin 
V1 to V5 or EOT value 
electrolytes (sodium, potassium, chloride, calcium) 
V1 to V5 or EOT value 
hsCRP 
V1 to V5 or EOT value 
fibrinogen 
V1 to V5 or EOT value 
haptoglobin 
V1 to V5 or EOT value 
lipase 
V1 to V5 or EOT value 
amylase 
V1 to V5 or EOT value 
Total Cholesterol 
V1 to V5 or EOT value 
HDL C 
V1 to V5 or EOT value 
TG 
V1 to V5 or EOT value 
LDL-C 
V1 to V5 or EOT value 
Serum Cystatin C 
V1 to V5 or EOT value 
Urinalysis 
Specific gravity 
V1 to V5 or EOT value 
pH 
V1 to V5 or EOT value 
Protein* 
V1 to V5 or EOT value 
Glucose* 
V1 to V5 or EOT value 
Ketones* 
V1 to V5 or EOT value 
bilirubin 
V1 to V5 or EOT value 
Urobilinogen* 
V1 to V5 or EOT value 
Blood* 
V1 to V5 or EOT value 
Nitrite* 
V1 to V5 or EOT value 
- 
 
Urinary albumin 
V1 to V5 or EOT value 
urinary creatinine 
V1 to V5 or EOT value 
urinary ACR* 
V1 to V5 or EOT value 


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using descriptive statistics for continuous variables. Clinical laboratory assessments will 
be classified with respect to laboratory reference ranges.  
Each parameter marked with an asterisk will be described at each visit as follows:  
 
eGFR: “≤60”, “>60” ml/min/1.73m² 
 
urinary ACR: “<30”, [30 – 300], ]300-1000], “>1000” mg/g 
 
Urinary parameters such as protein, glucose, ketones, urobilinogen, blood,  and 
nitrite: “negative”, “positive” 
Furthermore, for these parameters changes in these categories over time will be 
described by means of “shift tables” comparing the value at Visit 5 (Week 12) or EOT 
value to baseline value. 
For the laboratory parameters of significance (ALT, AST, GGT, 5-nucleotidase, CPK, and 
total and conjugated bilirubin), the value for each parameter will be assigned a 
classification according to whether the value is lower than, within, or higher than the 
corresponding reference range. Changes in these categories over time will be described 
by means of “shift tables” comparing the value at Visit 5 (Week 12) or EOT value to 
baseline value.   
For the laboratory parameters of clinical interest (ALT, AST, GGT, 5-nucleotidase, CPK, 
total and conjugated bilirubin) the number and percentage of patients reporting 
markedly abnormal laboratory values (<3xULN, between 3xULN and <5xULN, x>=5 ULN) 
will also be summarized by treatment arm. For these calculations, each subject may be 
counted once in the given laboratory parameter, as applicable.   
A by-patient listing, sorted by patient identifier, will present all laboratory results 
(scheduled or unscheduled) and will include flags to identify whether a result is outside 
of the normal range and whether it is markedly abnormal. 
9.5. 
VITAL SIGNS  
The following vital signs will be assessed at all visits: 
 
SBP (mmHg) 
 
DBP (mmHg) 
 
Pulse Rate (beats/min) 
 
Weight (Kg) 


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For all parameters, absolute values and change from baseline will be presented for 
scheduled visits using descriptive statistics for continuous variables. 
A by-patient listing, sorted by patient identifier, will be presented including all vital 
sign results (scheduled or unscheduled). 
9.6. 
ECG  
 A 12-Lead ECG will be performed at each scheduled study visit. The following ECG 
parameters will be assessed at each scheduled study visit visits: 
 
Overall ECG Evaluation 
 
Heart Rate (bpm) 
 
PR Interval (msec) 
 
QRS Duration (msec) 
 
QT Duration (msec) 
 
RR Duration (msec) 
 
QTcB - Bazett’s Correction Formula (msec) 
 
QTcF - Fridericia’s Correction Formula (msec) 
For all parameters, absolute values and change from baseline will be presented for 
scheduled visits using descriptive statistics for continuous variables. 
A by-patient listing, sorted by patient identifier, will be presented including all ECG 
results. A separate by-patient listing will also be presented, including patients with an 
abnormal Investigator interpretation of ECG results. 
9.7. 
PHYSICAL EXAMINATION 
A by-patient listing, sorted by patient identifier, will be presented including all physical 
examination results (scheduled or unscheduled) and will include flags to identify 
whether there were any new clinically significant findings. 
9.8. 
STANDARD DIET AND EXERCISE RECOMMENDATIONS 
A by-patient listing, sorted by patient identifier, will be presented including compliance 
to standard diet and exercise recommendations. 
 


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10. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
The Per-Protocol Population has been amended to analyze based on randomized 
treatment rather than actual treatment. 
A modified Intent-to-Treat population was added as in addition to a baseline measure, a 
post baseline measure is needed to assess the treatment effect. Thus, in the case of 
non similarity between ITT set and mITT set, all efficacy analyses will performed on the 
mITT set rather than on the ITT set. 
Definition of baseline has been clarified for all endpoints to be the last non missing 
value taken prior to first dose of study drug. 
Bile acids CDCA, Cholic Acid, Litocholic Acid and DCA will be analysed as total 
conjugated bile acids, total free bile acids and total bile acids.  These are defined 
within the SAP. 
Definition of EndPoint value has been clarified to be Visit 5 or the last post baseline 
measure under treatment regardless of premature withdrawal. 
Due to better stability, the measurement of lysophosphatidic acid has been replaced by 
autotaxin measurement.  


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11. 
REFERENCE LIST 
LaVange LM, Durham TA, Koch GG. Randomization-based nonparametric methods 
for the analysis of multicentre trials. Stat Methods Med Res. 2005;14(3):281-301. 
Zink R, Koch G. NParCov3: A SAS/IML Macro for nonparametric randomization-
based analysis of covariance. J Stat Softw. 2012:50(3). 
Analysis of Clinical Trials Using SAS: a Practical Guide Dmitrienko A, Moleberghs G, 
Chuang‐Stein C, Offen W (2005) ISBN 1590475046. 
 


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12. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications.   
12.1. 
GENERAL CONSIDERATIONS 
The following items need to be clarified upfront with the sponsor and Medical Writing 
and modified as per study requirements. 
 
A separate SAS program will be created for each output. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Word format. 
 
Numbering of TFLs will follow ICH E3 guidance. 
  
12.2. 
TABLE, LISTING, AND FIGURE FORMAT 
12.2.1. 
General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8  
 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
TLFs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as nonprintable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (eg, μ). Certain subscripts and 
superscripts (eg, cm2, Cmax) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
 
12.2.2. 
Headers 
 
All output should have the following header at the top left of each page: 


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<Sponsor Name> Protocol XXX 
study number xxx)                
Draft/Final Run <date> 
 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (ie, the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
 
The date output was generated should appear along with the program name as a 
footer on each page. 
 
12.2.3. 
Display Titles 
 
Each TLF should be identified by the designation and a numeral. (ie, Table 14.1.1).  
 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination (see also template 03.007C “Table of Contents  
for Tables Listings and Figures in Statistical Analysis Plan”). A decimal system (x.y 
and x.y.z) should be used to identify TLFs with related contents.  
 
The title is centered. The analysis set should be identified on the line immediately 
following the title. The title and table designation are single spaced.  
 
A solid line spanning the margins will separate the display titles from the column 
headers. There will be 1 blank line between the last title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
12.2.4. 
Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment arm columns and total column (if applicable). P-
values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 
 
Analysis set sizes will be presented for each treatment arm in the column heading as 
(N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of patients in the analysis set. 


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 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable). 
12.2.5. 
Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (eg, counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
12.2.5.2. Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment arms in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (eg, Medical History, Reasons for Discontinuation 
from the Study), then only those categories for which there is at least 1 subject 
represented in 1 or more groups should be included. 
 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 


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 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999 
 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (eg, 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0. A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment arm who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  
 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC alphabetically, assuming all terms are coded. Within the 
body system, drug class and SOC, medical history (by preferred term), drugs (by 
ATC1 code), and adverse events (by preferred term) should be displayed 
alphabetically. If incidence for more than 1 term is identical, they should then be 
sorted by highest incidence. Missing descriptive statistics or p-values which cannot 
be estimated should be reported as “-”. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant 
categories or just 1 category and the criteria for selecting the criteria. 
 
Where a category with a subheading (such as system organ class) has to be split over 
more than 1 page, output the subheading followed by “(cont)” at the top of each 
subsequent page. The overall summary statistics for the subheading should only be 
output on the first relevant page. 
 
12.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of patient number, visit/collection 
day, and visit/collection time. 
 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 


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 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (eg, 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
 
Units will be included where available 
 
12.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (eg, treatment mean change from Baseline) values will be displayed on 
the Y-axis. 
 
12.2.6. 
Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
 
Subject specific footnotes should be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than 6 lines of footnotes are planned, then a cover page may be used 
to display footnotes, and only those essential to comprehension of the data will be 
repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (ie, ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


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13. 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses. 
 SOP 03.010 and 
03.013 provide an overview of the development of such SAS programs. 
 SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
output by checking for their logic, efficiency and commenting and by review of the 
produced output. 
 


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14. 
INDEX OF TABLES 
Table 14.1.1.1 
Patient Disposition – Screening and Randomization 
Enrolled Set 
 
Table 14.1.1.2 
Patient Disposition 
Intent to Treat Set (ITT) 
 
Table 14.1.2.1 
Major protocol deviations 
Intent to Treat Set (ITT) 
 
Table 14.1.2.2 
Reasons for exclusion from analysis sets 
Intent to Treat Set (ITT) 
 
Table 14.1.3.1.1 
Subject demographic and baseline characteristics 
Safety set (SS) 
 
Table 14.1.3.1.2   
Subject demographic and baseline characteristics 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.3.1.3   
Subject demographic and baseline characteristics  
Per-Protocol set (PPS) 
 
Table 14.1.3.1.4   
Subject demographic and baseline characteristics  
Screen Failed subjects 
 
Table 14.1.3.1.5 
Screening and Baseline Laboratory Characteristics 
Safety set (SS) 
 
Table 14.1.3.1.6  
Screening and Baseline Laboratory Characteristics 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.3.1.7  
Screening and Baseline Laboratory Characteristics 
Per-Protocol set (PPS) 
 
 
Table 14.1.3.3.1 
Previous Medical History 
Safety Set (SS) 
 
Table 14.1.3.3.2   
Concomitant medical history 
Safety set (SS)  
 
Table 14.1.3.3.3 
Previous Medical History 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.3.2.2 
Concomitant medical history 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.4.1 
Prior Medication 
Safety Set (SS) 
 


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Table 14.1.4.2 
UDCA Medication at screening 
Safety Set (SS) 
 
Table 14.1.4.3 
Concomitant Medication 
Safety Set (SS) 
 
Table 14.1.4.4 
Prior Medication 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.4.5 
UDCA Medication at screening 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.4.6 
Concomitant Medication 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.1.5.1 
Treatment Compliance 
Safety Set (SS) 
 
Table 14.1.5.2 
Treatment Compliance 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.6.1 
Summary of Extent of Exposure to Study Drug 
Safety Set (SS) 
 
Table 14.1.6.2 
Summary of Extent of Exposure to Study Drug 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.1.1.1 
Change from Baseline in Serum Alkaline Phosphatase (ALP) at scheduled study visits 
Descriptive Statistics  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.1.1.2 
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) at EndPoint (Visit 5 or EOT value) 
Primary Efficacy Analysis (non-parametric randomization based ANCOVA)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.1.1.3  
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) at Scheduled Study Visits 
Descriptive Statistics  
Per Protocol Set (PPS) 
 
Table 14.2.1.1.4  
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) at EndPoint (Visit 5 or EOT value) 
Primary Efficacy Analysis (non-parametric randomization based ANCOVA)  
Per Protocol Set (PPS) 
 
Table 14.2.1.2.1 
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) at EndPoint (Visit 5 or EOT value) 


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Primary Efficacy Supportive Analysis (ANCOVA)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.1.2.2  
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) at EndPoint (Visit 5 or EOT value) 
Primary Efficacy Secondary Analysis (ANCOVA)  
Per Protocol Set (PPS) 
 
Table 14.2.1.2.3 
Absolute Change from Baseline in Serum Alkaline Phosphatase (ALP) at EndPoint (Visit 5 or EOT value) 
Secondary Efficacy Analysis (ANCOVA)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.1.2.4 
Absolute Change from Baseline in Serum Alkaline Phosphatase (ALP) at EndPoint (Visit 5 or EOT value) 
Secondary Efficacy Analysis (ANCOVA)  
Per Protocol Set (PPS) 
 
Table 14.2.2.1.1 
Response rate as defined by composite risk scores at EndPoint (Visit 5 or EOT value)   
Secondary Efficacy Analysis (Fishers Exact Test)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.1.2  
Response rate as defined by composite risk scores at EndPoint (Visit 5 or EOT value)   
Secondary Efficacy Analysis (Fishers Exact Test)  
Per Protocol Set (PPS) 
 
Table 14.2.2.2.1  
Response rate calculated using PBC risk scores at EndPoint (Visit 5 or EOT value)   
Secondary Efficacy Analysis (Fishers Exact Test)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.2.2  
Response rate calculated using PBC risk scores at EndPoint (Visit 5 or EOT value)   
Secondary Efficacy Analysis (Fishers Exact Test)  
Per Protocol Set (PPS) 
 
Table 14.2.2.3.1 
UK PBC Risk Score at EndPoint (Visit 5 or EOT value) 
Descriptive Statistics   
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.3.2 
UK PBC Risk Score at EndPoint (Visit 5 or EOT value) 
Descriptive Statistics   
Per Protocol Set (PPS) 
 
Table 14.2.2.4.1  
Response rate defined by normalized laboratory parameters; ALP, ALB and BIL at EndPoint  (Visit 5 or EOT 
value)  
Secondary Efficacy Analysis (Fishers Exact Test)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.4.2  
Response rate defined by normalized laboratory values; ALP, ALB and BIL at EndPoint  (Visit 5 or EOT value)   
Secondary Efficacy Analysis (Fishers Exact Test)  


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Per Protocol Set (PPS) 
 
Table 14.2.2.5.1  
Response rate defined by percentage reduction in Alkaline Phosphatase (ALP) at EndPoint  (Visit 5 or EOT 
value)   
Secondary Efficacy Analysis (Fishers Exact Test)  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.5.2  
Response rate defined by percentage reduction in Alkaline Phosphatase (ALP) at EndPoint  (Visit 5 or EOT 
value)   
Secondary Efficacy Analysis (Fishers Exact Test)  
Per Protocol Set (PPS) 
 
Table 14.2.2.6.1 
Change from Baseline in continuous secondary endpoints at scheduled study visits 
Descriptive Statistics  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.6.2 
Relative Change from Baseline in continuous secondary endpoints at EndPoint  (Visit 5 or EOT value) 
Descriptive Statistics and Secondary Efficacy Analysis (non-parametric randomization based ANCOVA)   
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.6.3 
Absolute Change from Baseline in continuous secondary endpoints at EndPoint  (Visit 5 or EOT value) 
Descriptive Statistics and Secondary Efficacy Analysis (ANCOVA)   
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.6.4 
Change from Baseline in continuous secondary endpoints at scheduled study visits 
Descriptive Statistics  
Per Protocol Set (PPS) 
 
Table 14.2.2.6.5 
Relative Change from Baseline in continuous secondary endpoints at EndPoint  (Visit 5 or EOT value) 
Descriptive Statistics and Secondary Efficacy Analysis (non-parametric randomization based ANCOVA)   
Per Protocol Set (PPS) 
 
 Table 14.2.2.6.6 
Absolute Change from Baseline in continuous secondary endpoints at EndPoint  (Visit 5 or EOT value) 
Descriptive Statistics and Secondary Efficacy Analysis (ANCOVA)   
Per Protocol Set (PPS) 
 
Table 14.2.2.7.1 
Absolute and relative Change from Baseline PRURITUS SCORING (5D ITCH SCALE) and Visual Analogue Scale 
Descriptive Statistics  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.7.2 
Absolute and relative Change from Baseline PRURITUS SCORING (5D ITCH SCALE) and Visual Analogue Scale 
Descriptive Statistics  
Per Protocol Set (PPS) 
 
Table 14.2.2.8.1 
Absolute and relative Change from Baseline in PBC40 Quality of Life Questionnaire (VAS) 


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Descriptive Statistics  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Table 14.2.2.8.2 
Absolute and relative Change from Baseline in PBC40 Quality of Life Questionnaire (VAS) 
Descriptive Statistics  
Per Protocol Set (PPS) 
 
Table 14.3.1.1 
Overall Summary of Adverse events 
Safety Set (SS) 
 
Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term 
Safety Set (SS) 
 
Table 14.3.1.3 
Summary of Related Treatment Emergent Adverse Events (TEAEs) by System Organ Class and Preferred 
Term 
Safety Set (SS) 
 
Table 14.3.1.4 
Summary of Serious Treatment Emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term 
Safety Set (SS) 
 
Table 14.3.1.5 
Summary of Related Serious Treatment Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term 
Safety Set (SS) 
 
Table 14.3.1.6 
Summary of Treatment Emergent Adverse Events (TEAEs) leading to permanent withdrawal of study drug by 
System Organ Class and Preferred Term 
Safety Set (SS) 
 
14.3.1.7 
Summary of Treatment Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term and 
Maximum Intensity 
Safety Set (SS) 
 
Table 14.3.2.1 
Deaths, listing  
Safety Set (SS) 
 
Table 14.3.2.2 
Listing of Serious Treatment Emergent Adverse Events (Serious TEAE) 
Safety Set (SS) 
 
Table 14.3.2.3 
Listing of Non-Treatment Emergent Serious Adverse Events (SAEs) 
Safety Set (SS) 
 
Table 14.3.2.4 
Listing of Treatment Emergent Adverse Events Leading to Temporary or Permanent Withdrawal of Study 
Drug 
Safety Set (SS) 


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Table 14.3.4.1.1.1 
Summary of Hematology Laboratory Parameters 
Safety Set (SS) 
 
Table 14.3.4.1.2.1 
Summary of Biochemistry Laboratory Parameters 
Safety Set (SS) 
 
Table 14.3.4.1.3.1 
Summary of Urinalysis Laboratory Parameters 
Safety Set (SS) 
 
Table 14.3.4.1.1.2 
Abnormal classification summary of Laboratory Parameters of Clinical Interest 
Safety Set (SS) 
 
Table 14.3.4.1.1.3 
Shift Table of L/N/H Classification for Laboratory Parameters of Clinical Interest 
Safety Population (SS) 
 
Table 14.3.4.1.1.4 
Listing of Patients with at Least One Clinically Significant Hematology Laboratory Parameter 
Safety Set (SS) 
 
Table 14.3.4.1.2.4 
Listing of Patients with at Least One Clinically Significant Biochemistry Laboratory Parameters 
Safety Set (SS) 
 
Table 14.3.4.1.3.4 
Listing of Patients with at Least One Clinically Significant Urinalysis Laboratory Parameters 
Safety Set (SS) 
 
Table 14.3.4.2.1 
Summary of Vital Sign Parameters 
Safety Set (SS) 
 
Table 14.3.4.2.2 
Summary of ECG Parameters 
Safety Set (SS) 
 
 
 
 
 
 
 
 
 
 
 
 


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15. 
INDEX OF FIGURES 
Figure 14.4.1 
Summary of Primary Efficacy Parameter, Absolute and Relative Change from Baseline in Serum Alkaline Phosphatase 
(ALP) 
Box and Whisker plot 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Figure 14.4.2 
Summary of Continuous Secondary Efficacy Parameters, Absolute and Relative Change from Baseline  
Box and Whisker plot 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
 


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16. 
INDEX OF LISTINGS 
Listing 16.2.1.1 
Patient Disposition – Screen Failures 
Enrolled Subjects 
 
Listing 16.2.1.2 
Patient Disposition  
Intent to treat Set (ITT) 
 
Listing 16.2.2.1 
Protocol Deviations  
Intent to treat Set  ITT) 
 
Listing 16.2.3.1 
Violation of Eligibility Criteria-Inclusion/ Exclusion Criteria 
Intent to treat Set (ITT)  
 
Listing 16.2.3.2 
Exclusion from analysis sets 
Intent to treat Set (ITT)  
 
Listing 16.2.4.1 
Demographics  
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.4.2 
Other Baseline Characteristics: Screening and baseline laboratory characteristics 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.4.3 
Other Baseline Characteristics: Serology labs 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.4.4 
Pregnancy test 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.4.5 
Medical History (Prior and Concomitant) 
Intent to treat Set  (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.4.7 
Standard Diet and Exercise recommendations 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.4.8 
Prior and concomitant medications 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
 
Listing 16.2.5.1 
Randomization and treatment administration 
Safety Set (SS) 
 


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Listing 16.2.5.2 
Drug accountability 
Safety Set (SS) 
 
Listing 16.2.5.3 
IP Compliance 
Safety Set (SS) 
 
Listing 16.2.6.1 
Primary Efficacy Endpoint: Serum Alkaline Phosphotase 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.6.2 
Secondary Efficacy Endpoints: Response Rates 
Intent to treat Set (ITT) / Modified Intent to treat Set (mITT) 
 
Listing 16.2.6.3 
Secondary Efficacy Endpoints: Absolute and relative change From Baseline 
Intent to treat Set (ITT) /  Modified Intent to treat Set (mITT) 
 
Listing 16.2.6.4 
Secondary Efficacy Endpoints: Absolute and relative change From Baseline Priuritus Scoring (5D Itch Scale) 
Intent to treat Set  (ITT) /  Modified Intent to treat Set (mITT) 
 
Listing 16.2.6.5 
Secondary Efficacy Endpoints: Absolute and relative change From Baseline PBC40 QOL questionaire 
Intent to treat Set (ITT) /  Modified Intent to treat Set (mITT) 
 
Listing 16.2.7.1 
Listing of All Adverse Events (AE) 
Safety Set (SS) 
 
Listing 16.2.8.1.1 
Listing of Hematology Laboratory Parameters 
Safety Set (SS) 
 
Listing 16.2.8.1.2 
Listing of Biochemistry Laboratory Parameters 
Safety Set (SS) 
 
Listing 16.2.8.1.3 
Listing of Urinalysis Laboratory Parameters 
Safety Set (SS) 
 
Listing 16.2.8.1.4 
Listing of Liver Markers Laboratory Parameters 
Safety Set (SS) 
 
Listing 16.2.8.1.5 
Listing of Inflammatory marker Laboratory Parameters 
Safety Set (SS) 
 
Listing 16.2.8.1.6 
Listing of Other Laboratory Parameters 
Safety Set (SS) 
 


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Listing 16.2.8.2.1 
Listing of Vital Signs 
Safety Set (SS) 
 
Listing 16.2.8.2.2 
Listing of Electrocardiogram (ECG) parameters 
Safety Set (SS) 
 
Listing 16.2.8.2.3 
Listing of Physical Examination 
Safety Set (SS) 
 
Listing 16.2.8.2.4 
Listing of Standard Diet and Exercise Recommendations 
Safety Set (SS) 
 
 
 
 
 
 
 
 


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17. 
APPENDICES 
List all appendices as needed.