A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients With Primary Biliary Cholangitis With Inadequate Response or Intolerance to Ursodeoxycholic Acid
Phase: PHASE3
Conditions: Primary Biliary Cirrhosis
Sponsor: Ipsen



 
 
 
 
 
Clinical Trial GFT505B-319-1 
Protocol version 6.0 13 February 2024 
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Principal Investigator Signature Page 
  
 
I have read and agree to Protocol N° GFT505B-319-1 Version 6.0 with Amendment 5 entitled ‘A Double-
blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the 
Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate 
Response or Intolerance to Ursodeoxycholic Acid’. I am aware of my responsibilities as an investigator 
under the guidelines of Good Clinical Practice (GCP), local regulations (as applicable) and the study 
protocol. I agree to conduct the study according to these guidelines and to appropriately direct and 
assist the staff under my control, who will be involved in the study. 
 
NAME:   
TITLE: 
[PRINCIPAL] 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
 
 
 

 
 
 
 
 
Clinical Trial GFT505B-319-1 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
 
DOCUMENT HISTORY 
Document 
Version Date 
Status 
Amendment 5 
6.0 
13 February 2024 
Effective 
Amendment 4 
5.0 
20 December 2022 
Superseded, Replaced by V6.0 
Amendment 3 
4.0 
20 September 2022 
Superseded, Replaced by V5.0 
Amendment 2 
3.0 
18 March 2022 
Superseded, Replaced by V4.0 
Amendment 1 
2.0 
11 December 2020 
Superseded, Replaced by V3.0 
Original Protocol 
1.0 
22 July 2020 
- 
 
 
Amendment 5 (13 February 2024) 
 
This amendment is considered to be non-substantial based on the criteria set forth in applicable 
regulations because it neither significantly impacts the safety or rights of participants nor the reliability 
and robustness of the data generated in the clinical trial. 
 
 
Overall Rationale for the Amendment: 
 
The protocol was amended to incorporate the information from the local addendum #1 for Germany 
dated 30 May 2023 and the typographical errors in the protocol version 4.0 dated 20 September 2022 
until now mentioned separately in an erratum to the protocol. 
 
Summary change table from previous version of the protocol 
 
Any new or amended text in the protocol is indicated in bold (IS column). Deletions are marked in 
strikeout text (WAS column). Minor formatting and editing are not included. 
 

 
 
 
 
 
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Amendments to be implemented in the following documents 
 
Informed consent form  
Yes  
  No  
 
Case report form (CRF)  
Yes  
  No  
 
Statistical analysis plan (SAP)  
Yes  
  No  
 
 
 
 

 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
 
Ab 
Antibody 
ABV 
alcohol by volume 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AFP 
Alfa-fetoprotein 
AIH 
autoimmune hepatitis 
ALCOA 
attributable, legible, contemporaneous, original and accurate 
ALD 
alcoholic liver disease 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
anti-mitochondrial antibodies 
ANA 
antinuclear antibodies 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
AUCss 
Area Under Curve steady state 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C4 
serum 7α-hydroxy-4-cholesten-3-one 
CA 
cholic acid 
CCl4 
carbon tetrachloride 
CDCA 
chenodeoxycholic acid 
CEC 
clinical events committee 
CFR 
Code of Federal Regulations 
CI 
confidence interval  
CK-18 
cytokeratin-18 
CKD-EPI 
Chronic Kidney Disease - Epidemiology Collaboration 
CPK 
creatine phosphokinase  
CRF 
case report form 
CRO 
clinical research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTA 
Clinical Trial Agreement 
CTFG 
Clinical Trial Facilitation Group 
CYP 
cytochrome P450 
DB 
double blind 
DCA 
deoxycholic acid 
DDI 
drug-drug interaction 
DEXA 
dual-energy X-ray absorptiometry 
DILI 
drug-induced liver injury 
DSMB 
data safety monitoring board 
DSUR 
development safety update report 
EAIR 
exposure adjusted incidence rates 
EASL 
European Association for the Study of the Liver 

 
 
 
 
 
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ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ELF 
enhanced liver fibrosis 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study  
EOT 
end of treatment 
ePRO 
electronic patient-reported outcomes 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
FGF19 
fibroblast growth factor 19 
FPG 
Fasting plasma glucose 
GCA 
glycocholic acid 
GCDCA 
glycochenodeoxycholic acid 
GCP 
Good Clinical Practice 
GDCA 
glycodeoxycholic acid 
GGT 
gamma-glutamyl transferase 
GLCA 
glycolithocholic acid 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HCV Ab 
hepatitis C virus Antibody 
HDL-C 
High-density lipoprotein cholesterol 
hHSC 
human hepatic stellate cells 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
hsCRP 
high sensitivity C-reactive protein 
IB  
Investigator’s Brochure  
ICE 
Intercurrent event 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IXRS 
interactive voice/web response system 
LCA 
lithocholic acid 
LDL-C 
low-density lipoprotein cholesterol 
LLN 
lower limit of normal 
LTE 
long term extension 
LVDB 
last visit double blind 

 
 
 
 
 
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MAR 
missing at random 
MCP 
monocyte chemotactic protein 
MDR3 
multidrug resistance protein type 3 
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
MELD-Na 
Model for End-Stage Liver Disease-Sodium 
MMRM 
mixed model with repeated measurement 
MRI 
magnetic resonance imaging 
NA 
not applicable 
NASH 
nonalcoholic steatohepatitis 
NF-κB 
nuclear factor kappa B 
NOAEL 
no observed adverse effect level 
NRS 
numeric rating scale 
OATP1B3  
organic anion transporting polypeptide 1B3 
OCA 
obeticholic acid 
PAI 
Plasminogen activator inhibitor 
PBC 
Primary biliary cholangitis 
PBI 
placebo-based multiple imputation 
PDGF 
platelet-derived growth factor 
PGIC 
patient global impression of change 
PGIS 
patient global impression of severity 
PK 
pharmacokinetics 
PKS 
pharmacokinetics set 
PP 
per-protocol 
PPAR 
peroxisome proliferator-activated receptor 
PRO 
patient reported outcome 
PROMIS 
Patient Reported Outcome Measurement Information System 
PSC 
Primary sclerosing cholangitis 
PT 
prothrombin time 
QoL 
quality of life 
RNA 
ribonucleic acid 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
Source data verification 
SMA 
smooth muscle antibodies 
SOP 
standard operating procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reaction 
SV 
screening visit 
TB 
total bilirubin 
TC 
total cholesterol 
TCA 
taurocholic acid 
TCDCA 
taurochenodeoxycholic acid 
TDCA 
taurodeoxycholic acid 

 
 
 
 
 
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TE 
transient elastography 
TG 
triglycerides 
TGF-β 
transforming growth factor beta 
TIPS 
transjugular intrahepatic portosystemic shunts 
TLCA 
taurolithocholic acid 
TNF 
tumor necrosis factor-alpha 
UDCA 
ursodeoxycholic acid 
UK 
United Kingdom 
ULN 
upper limit of normal 
Urine ACR 
Urine albumin to creatinine ratio 
UV-LLNA 
UV- local lymph node assay 
VLDL 
very low density lipoprotein 
WBC 
white blood count 
WOCBP 
women of childbearing potential 
 
 

 
 
 
 
 
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CLINICAL STUDY SYNOPSIS 
Sponsor: 
IPSEN PHARMA SAS 
Study Drug: 
Elafibranor  
Protocol Number: 
GFT505B-319-1 
Title of the study: 
A Double-blind, Randomized, Placebo-Controlled Study and Open-label Long Term Extension to 
Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis 
with Inadequate Response or Intolerance to Ursodeoxycholic Acid 
Phase: 3 
Indication: Primary Biliary Cholangitis (PBC) 
Study Design and dose levels: 
This is a phase 3 double-blind (DB), randomized, placebo-controlled study with an open-label long 
term extension (LTE) evaluating the efficacy and safety of Elafibranor 80 mg once daily versus 
placebo in patients with PBC and inadequate response or intolerance to ursodeoxycholic acid 
(UDCA). 
In the DB period, patients will be randomized in a 2:1 ratio to receive Elafibranor 80 mg or placebo, 
once daily. The DB period will last until the last completed week 52 (V6) or until a maximum of 
104 weeks DB period, whichever happens first, to further collect safety and clinical outcomes data 
in a DB manner. After the DB period, all patients will receive Elafibranor 80 mg daily for up to 5 
years during the LTE period. 
When applicable, patients should continue their pre-study dose of UDCA throughout the study 
participation. 
Schema 1: GFT505B-319-1 Study Design 
Footnotes:  
a. If receiving UDCA at randomization, continue throughout study participation 
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the 
last completed V6 (W52), whichever occurs first 
c. The LTE duration is up to 5 years after end of the DB period or until the patient’s total treatment 
duration is 6 years, whichever occurs first 
d. Safety follow-up 4 weeks after last dose of study drug 
 
For exploratory purposes, all patients enrolled will be invited to participate in the following 
voluntary procedures, which will require separate informed consent: 
- collection of biobank samples for additional research on biomarkers associated with PBC 
- collection of liver biopsy samples (at baseline and week 52)  

 
 
 
 
 
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Route of Administration: Oral 
Primary Objective: 
To evaluate the effect of Elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint 
over 52 weeks of the treatment compared to placebo 
 
Key Secondary Objectives: 
To evaluate the effect of Elafibranor (80 mg/day) on normalisation of alkaline phosphatase (ALP) 
over 52 weeks of the treatment compared to placebo  
To evaluate the effect of Elafibranor (80 mg/day) on pruritus through 52 weeks of the treatment 
compared to placebo in patients with baseline PBC Worst Itch NRS score ≥4 
To evaluate the effect of Elafibranor (80 mg/day) on pruritus through 24 weeks of the treatment 
compared to placebo  in patients with baseline PBC Worst Itch NRS score ≥4 
 
Secondary Objectives: 
1) To evaluate the effect of Elafibranor (80 mg/day) over 52 weeks of treatment compared to 
placebo on: 
a) Hepatobiliary injury and liver function markers 
b) Inflammation and hepatic fibrosis 
c) Lipid parameters 
d) Bile acids 
e) Pruritus Patient Reported Outcomes (PROs) 
f) 
Patient-reported Fatigue  
g) Patient-reported Sleep  
h) Health-related Quality of Life (HRQoL) 
i) 
Health utility 
j) 
Markers of bone turnover and bone density 
k) Safety and tolerability 
2) To determine the pharmacokinetics (PK) parameters of elafibranor and its active metabolite 
GFT1007, at steady state following daily oral administration at 80 mg in PBC patients 
3) To evaluate the effect of Elafibranor (80 mg/day) during the LTE period on: 
a) Safety and tolerability 
b) Maintenance of efficacy from the DB period 
 
Exploratory objectives (for the patients having consented to participate): 
1) To constitute a biobank for discovery and validation of biomarkers associated with PBC 
2) Based on histology: 
a) 
To assist the interpretation of efficacy and safety results of elafibranor 
b) 
To explore the correlation of fibrosis scores with non-invasive markers of fibrosis (liver 
stiffness, ELF test and ProC3)  
 

 
 
 
 
 
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Patient Population: Patients with PBC and inadequate response or intolerance to UDCA 
Number of Randomized Patients (Approximately): 150 
Number of Participating Centers (Approximately): 120 
Number of Participating Countries (Approximately): 15 
Study Duration per Patient: Up to approximately 6 years, or 328 weeks (2 to 12 weeks for the 
screening period, 52 to 104 weeks for the DB period, 208 to 260 weeks for the LTE period, and 4 
weeks for safety follow-up).  

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Inclusion Criteria: 
Patients must meet all of the following inclusion criteria to be eligible for randomization into the 
study: 
1) Must have provided written informed consent and agree to comply with the study 
protocol 
2) Males or females age of 18 to 75 years inclusive at first Screening Visit (SV) 
3) PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic 
criteria: 
a. 
History of elevated ALP levels for ≥ 6 months prior to randomization (V1) 
b. 
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 (ANA) 
c. 
Liver biopsy consistent with PBC 
4) ALP ≥ 1.67x upper limit of normal (ULN) (based on two values – see section 3.5.1)  
5) Total bilirubin (TB) ≤ 2x ULN 
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term 
clinical outcomes or moderate disease stage, approximately 10% of randomized 
patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin 
< lower limit of normal [LLN]) and approximately 20% will have a TB > 0.6 x ULN 
(patients at risk of progression) 
6) Must have at least 4 available values for PBC Worst Itch Numeric Rating Scale (NRS) 
during each of the 7 day intervals in the 14 days prior to randomization (V1), for a 
total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to 
randomization (V1)  
7) UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable 
to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per 
country standard-of-care dosing) 
8) If on colchicine must be on a stable dose for ≥ 3 months prior to screening 
9) Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone 
or sertraline) must be on a stable dose for ≥ 3 months prior to screening 
10) Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior 
to screening 
11) Females participating in this study must be of non-child bearing potential or must 
be using highly effective contraception for the full duration of the study and for 1 
month after the last drug intake: 
• 
Non-child bearing potential: cessation of menses for at least 12 months due to 
ovarian failure or surgical sterilization such as bilateral oophorectomy, or 
hysterectomy 
• 
Highly effective contraception includes:  
a. Combined 
(estrogen 
and 
progrestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation, oral, intravaginal 
or transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation, oral, injectable or implantable 
c. Intrauterine device (IUD) 
d. Intrauterine hormone release system (IUS) 
e. Bilateral tubal occlusion 
f. 
Vasectomized partner 

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g. Sexual abstinence, if required by local IRB/IEC regulations and/or 
considered adequate by National laws (the reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient) 
 
12) For patients who consent to have liver biopsy samples collected, patients in whom 
it is safe and practical to proceed with a liver biopsy, and who agree to have: 
• 
1 liver biopsy during the Screening Period (if no historical biopsy within 6 
months before screening is available) 
• 
1 liver biopsy after 52 weeks of treatment 
Exclusion Criteria: 
Patients presenting any of the following exclusion criteria will not be eligible for randomization into 
the study: 
1) History or presence of other concomitant liver disease including: 
a) Positive anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibodies or 
positive hepatitis B surface antigen (HBsAg) or positive anti-hepatitis C virus 
(HCV) ribonucleic acid (RNA) (tested for in case of known cured HCV infection 
or positive HCV Ab at screening) 
b) Primary sclerosing cholangitis (PSC) 
c) Alcoholic liver disease (ALD) 
d) Autoimmune hepatitis (AIH) or if treated for an overlap of PBC with AIH, or if 
there is suspicion and evidence of overlap AIH features, that cannot be 
explained alone by insufficient response to UDCA 
e) Nonalcoholic steatohepatitis (NASH) 
f) 
Gilbert’s Syndrome (exclusion due to interpretability of bilirubin levels) 
g) Known history of alpha-1 antitrypsin deficiency 
2) Clinically significant hepatic decompensation, including: 
a) History of liver transplantation, current placement on a liver transplant list, 
current Model for End-Stage Liver Disease-Sodium (MELD-Na) score ≥ 12 
linked to hepatic impairment 
b) Patients with cirrhosis/portal hypertension complications, including known 
esophageal varices, ascites, history of variceal bleeds or related interventions 
(e.g., insertion of variceal bands or transjugular intrahepatic portosystemic 
shunts [TIPS]), and hepatic encephalopathy, history or presence of 
spontaneous bacterial peritonitis, hepatocellular carcinoma 
c) Hepatorenal syndrome (type I or II) 
3) Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s 
disease) or which may diminish life expectancy to < 2 years, including known 
cancers 
4) Patient has a positive test for Human Immunodeficiency Virus (HIV) Type 1 or 2 
at screening, or patient is known to have tested positive for HIV 
5) Evidence of any other unstable or untreated clinically significant immunological, 
endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as 
evaluated by the investigator; other clinically significant medical conditions that 
are not well controlled  

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6) 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 screening visit (SV1) 
7) For female patients: known pregnancy, or has a positive serum pregnancy test, or 
lactating 
8) Administration of the following medications are prohibited as specified below: 
a) 2 months prior to screening: fibrates and glitazones 
b) 3 months prior to screening: azathioprine, cyclosporine, methotrexate, 
mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids 
(parenteral and oral chronic administration only); potentially hepatotoxic drugs 
(including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin) 
c) 12 months prior to screening: antibodies or immunotherapy directed against 
interleukins (ILs) or other cytokines or chemokines 
d) For patients with previous exposure to OCA, OCA should be discontinued 3 
months prior to screening 
9) Patients who are currently participating in, plan to participate in, or have 
participated in an investigational drug study or medical device study containing 
active substance within 30 days or five half-lives, whichever is longer, prior to 
screening; for patients with previous exposure to seladelpar, seladelpar should be 
discontinued 3 months prior to screening. 
10) Patients with previous exposure to elafibranor 
11) SV value of alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) > 5x ULN 
12) For patients with AT or TB values >ULN at SV1, Variability of AT or TB > 40% (see 
section 3.5.1) 
13) SV value of albumin < 3.0 g/dL 
14) Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin 
< LLN) 
15) SV value of international normalized ratio (INR) > 1.3 due to altered hepatic 
function 
16) SV value of creatine phosphokinase CPK > 2X ULN 
17) Screening serum creatinine > 1.5 mg/dL 
18) Significant renal disease, including nephritic syndrome, chronic kidney disease 
(defined as patients with markers of kidney failure damage or estimated 
glomerular filtration rate [eGFR] < 60 mL/min/1,73 m2) calculated by modification 
of diet in renal disease (MDRD) 
19) Platelet count < 150 X 103/µL 
20) Alfa-fetoprotein (AFP) > 20 ng/mL with 4-phase liver computed tomography (CT) 
or magnetic resonance imaging (MRI) suggesting presence of liver cancer 
21) Known hypersensitivity to the investigational product or to any of the formulation 
excipients of the elafibranor or placebo tablet 
22) Mental instability or incompetence, such that the validity of informed consent or 
ability to be compliant with the study is uncertain 
Randomization: 

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Patients who satisfy all eligibility criteria will be randomized in a 2:1 ratio to one of the following 
groups: 
• 
Elafibranor 80 mg 
• 
Placebo 
A central randomization system (Interactive Voice/Web Response system (IXRS)) will be used. 
The randomization will be stratified on two factors (ALP > 3 x ULN or bilirubin > ULN and Worst 
Itch score averaged - over the 14 days preceding baseline - ≥ 4) at baseline (V1). During the LTE 
period, all patients will receive Elafibranor 80 mg, once daily, for up to 5 years. 
To ensure inclusion of a relevant ratio of patients with substantial risk of long term clinical outcomes 
or moderate disease stage, approximately 15 patients (approximately10% of the total randomized 
patients) will present a TB above ULN or albumin below LLN and approximately 30 patients 
(approximately 20% of the total randomized patients) will present a TB above 0.6x ULN. 
 
Criteria for Evaluation: 
Primary Endpoint: 
Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease 
≥ 15%. 
Secondary Endpoints: 
Key Secondary Endpoints: 
 
1) Response to treatment based on ALP normalization at week 52. 
 
2) Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with 
baseline PBC Worst Itch NRS score ≥4. 
3) Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with 
baseline PBC Worst Itch NRS score ≥4  
Other Secondary Endpoints: 
1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks 
2) ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52 
3) Response to treatment at week 52 according to: 
a) ALP < 1.5x ULN, ALP decrease ≥ 40% and TB ≤ ULN 
b) ALP < 3x ULN, AST <2x ULN and TB < 1 mg/dL (Paris I) 
c) ALP ≤ 1.5x ULN, AST ≤ 1.5x ULN and TB ≤ ULN (Paris II) 
d) TB response rate of 15% change 
e) Normalization of abnormal TB and/or albumin (Rotterdam) 
f) 
TB ≤ 0.6 x ULN 
g) ALP ≤ 1.67x ULN and TB ≤ 1 mg/dL [1] 
h) No worsening of TB defined as level of TB ≤ ULN at week 52 or no increase from baseline of 
more than 0.1XULN at week 52 
i) 
Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin and INR 
4) PBC risk scores at week 52: United Kingdom (UK) PBC score [2] and GLOBE score [3]  

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5) Response based on bilirubin normalization (TB ≤ ULN) at week 52 
6) Response based on albumin normalization at week 52 
7) Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST, 
ALT, gamma-glutamyl transferase (GGT), 5’ NT, total and conjugated bilirubin, albumin, INR and 
ALP fractionated (hepatic) 
8) Change from baseline to week 52 in biomarkers of inflammation as measured by high-sensitivity 
C-Reactive Protein (hsCRP), fibrinogen, haptoglobin and tumor necrosis factor-alpha (TNF-) 
9) Change from baseline to week 52 in immune response as measured by immunoglobulin G (IgG) 
and IgM 
10) Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis 
as measured by enhanced liver fibrosis (ELF)(HA, PIINP, TIMP-1), plasminogen activator 
inhibitor-1 (PAI-1), transforming growth factor beta (TGF-β), cytokeratin-18 (CK-18) (M65 and 
M30), Pro-C3 and liver stiffness measured by Transient Elastography (TE) (continuous) 
11) Change from baseline to week 52 in lipid parameters as measured by total cholesterol (TC), low-
density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), calculated 
VLDL-C and TG 
12) Change from baseline to week 52 in fasting plasma glucose (FPG) 
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured 
by bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF-
19) 
14) Proportion of patients with no worsening of pruritus from baseline through week 52 and through 
week 24 as measured by the PBC Worst Itch NRS 
15) Proportion of responders in PBC Worst Itch NRS  according to clinically meaningful change; at 
least 30% reduction; and one point, two points or three points decrease in score from baseline  
through week 52 and through week 24 in patients with a baseline NRS score≥ 4 
16) Change from baseline to week 52 in 5D-Itch 
17) Change from baseline to week 52 in Patient Reported Outcome Measurement Information System 
(PROMIS) Fatigue Short Form 7a 
18) Change from baseline to week 52 in the Epworth Sleepiness Scale (ESS) 
19) Change from baseline to week 52 in PBC-40 
20) Change from baseline to week 52 in health utility as measured by the EQ-5D-5L 
21) Change from baseline to week 52 in serum markers of bone turnover and in bone density (hip 
and lumbar) assessed by DEXA scanning  
22) Onset of clinical outcomes described as a composite endpoint composed of: 
a) MELD-Na > 14 for patients with baseline MELD-Na <12 
b) Liver transplant 
c) Uncontrolled ascites requiring treatment  
d) Hospitalization for new onset or recurrence of any of the following: 
i)  variceal bleed 
ii) hepatic encephalopathy defined as West-Haven/Conn score of 2 or more 
iii) spontaneous bacterial peritonitis 
e) Death 
23) Safety and tolerability as assessed by 

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a) Serious adverse events (SAEs), adverse events (AEs), adverse events of special interest 
(AESIs), physical examination, vital signs, medical history, electrocardiogram (ECG) 
b) Chemistry and hematology 
c) Liver markers 
d) Renal biomarkers (including urinalysis) 
e) Other biochemical safety markers 
24) PK assessed by GFT505 and GF1007 concentrations measurement in plasma 
 
Additionally, apart from histology (if applicable) and PK assessments, the same endpoints as for the 
DB period will be collected over the LTE period to assess the maintenance of efficacy and safety of 
the treatment. 
 
Exploratory Endpoints (related to histological assessements): 
1) Change from baseline in the histological scores: 
a) Fibrosis stage according to Nakanuma scoring  
b) Bile duct loss score 
c) Cholangitis activity 
d) Interface Hepatitis activity 
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct loss score) 
f) Other exploratory scores (Fibrosis according to Ishak scoring, portal inflammation, ductular 
reaction, cholestasis, concentric periductal fibrosis) 
2) Correlation between histological fibrosis scores and non-invasive markers of fibrosis  
(liver stiffness, ELF test, proC3) 
 
 
Data Safety Monitoring Board (DSMB): 
An independent DSMB will be established in order to review the progress of the study and to 
perform a safety data review (including review of the adjudication reports issued from the clinical 
events committee (CEC) on a regular basis during the study to protect patient welfare and preserve 
study integrity.  
The DSMB will consist of at least 5 experienced physicians (1 endocrinologist, 1 cardiologist, 1 
hepatologist, 1 oncologist, and 1 nephrologist) and 1 statistician, all of whom will be independent 
from the conduct of the study. The DSMB Charter will define the membership, role, responsibilities, 
rules, and tasks of the DSMB. 
Clinical Event committee (CEC) 
The CEC will conduct adjudication of the clinical outcomes  and DILI (Drug Induced Liver Injury) 
events. The CEC assessment and adjudication will occur in a blinded (during DB period) and consistent 
and unbiased manner throughout the course of the study to determine whether the event meets the 
protocol specified criteria. The CEC will be comprised of 3 hepatologists; all of them will be 
independent from the conduct of the study. 
 
Statistical considerations: 
Determination of the sample size 
The assumptions used for the determination of the sample size are: 
• 
an expected response rate in the placebo group slightly higher than that in the phase 3 pivotal 
study supporting the regulatory approval of OCA (10%) [4], 
• 
an expected response rate in the elafibranor group at least similar to OCA (47%). 

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The response rates from phase 3 pivotal study supporting the regulatory approval of OCA has been 
estimated after imputation of missing data as non-response. 
One hundred and fifty patients (100 elafibranor and 50 placebo) allow to achieve at least 90% power 
to demonstrate a statistically significant between group difference of 35% (47% in elafibranor group 
vs 12% in placebo group) in the response rate at week 52 of the primary efficacy endpoint with a 
two-sided alpha of 0.05 and using an exact Fisher test. 
In addition, assuming 1/50 (2.0%) patient in the placebo group with ALP normalization at week 52 
(key secondary endpoint), 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power 
to detect a statistically significant between group difference of 20.0% at a two-sided 0.05 alpha level. 
Assuming a pooled standard deviation (SD) of 2.3 points, 60 patients (40 Elafibranor vs 20 placebo) 
with baseline PBC Worst Itch NRS score ≥4 provide at least 80% power to detect a statistically 
significant between group difference of 1.8 points in mean change from baseline in PBC Worst Itch 
NRS score (second key secondary endpoint) at a two-sided 0.05 alpha level. It is assumed that the 
same assumptions would apply to the two key secondary endpoints for pruritus (through week 52 
and through week 24). 
Analysis sets: 
• 
Screened set: all patients who sign informed consent. This set will be used to summarize 
disposition. 
• 
Intent-to-treat (ITT) set: All randomized subjects. 
• 
Per-protocol (PP) set: All subjects from the ITT set without any major protocol deviation 
affecting the primary efficacy endpoint. 
• 
Safety set (SS): All subjects who were administered at least one dose of study drug. 
• 
Pharmacokinetics set (PKS): All patients who were administered at least one dose of study 
drug and have at least one post-dose PK sample. Moreover, patients of the PK set must 
have data for time of dosing, time of sampling and amount of drug administered. Whereas 
all patients are sampled in order to maintain the blind, the pharmacokinetics set applies 
only to patients under elafibranor. 
• 
Exploratory (Histological) set: All subjects from the ITT set who consent to have liver 
biopsy samples collected at baseline and/or week 52.   
Efficacy analysis: 
DB treatment period 
The primary and secondary efficacy analyses will be performed primarily on the ITT set and 
secondarily on the PP set. Each efficacy endpoint will be evaluated up to week 52. For patients 
who completed additional visits during the DB period, descriptive statistics will be presented up to 
the end of the DB period.  
• 
Primary efficacy endpoint 
The response rates (ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 15%) at week 52 will be 
compared between the treatment groups using the exact Cochran-Mantel-Haentzel test stratified by 
the randomization strata. Patients who stopped prematurely the study treatment will be considered 
as non-responders. 
A sensitivity analysis to the statistical model will be performed using an exact logistic regression model 
with treatment group and randomization strata as factors. 
Three supplementary/sensitivity analyses will be assessed using relevant multiple imputation methods 
to manage missing data. One will assume Missing At Random (MAR) and use multiple imputation to 

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impute values as if subjects would follow their initial treatment. A second one will impute values using 
the information from the placebo group. The third one will be a tipping point analysis to explore a 
number of scenarios about the missing outcomes. 
A last supplementary analysis will use outcome value at week 52 regardless of treatment 
discontinuation or use of rescue therapy. 
• 
Key secondary endpoints 
The response rates (proportion of patients with ALP normalization) at week 52 will be compared 
between the treatment groups using the same method as for the primary efficacy endpoint, including 
sensitivity and supplementary analyses. 
The change from baseline in PBC Worst Itch NRS score through week 52 will be summarized by 
treatment group and will be compared using a Mixed Model with Repeated Measurement (MMRM) 
with stratification factors as fixed factors. A supplementary analysis based on treatment policy will 
use outcome values at week 52 regardless of treatment discontinuation or use of rescue therapy. The 
same analyses will be repeated for the change from baseline in PBC Worst Itch NRS score through 
week 24. 
• 
Other secondary endpoints 
The continuous endpoints will be compared between the treatment groups using the MMRM. 
The categorical endpoints will be analyzed using the exact Cochran-Mantel-Haentzel test stratified by 
the randomization strata. As for the primary endpoint, the subject who do not complete the study 
will be considered as non-responders/treatment failures. 
• 
Control of type I error rate 
The fixed-sequence testing approach will be used to control the overall Type I error rate at a two-
sided 0.05 level. If the primary endpoint is statistically significant at a two-sided 0.05 level, the first 
key secondary endpoint (ALP normalization) will be tested at the same level. If the first key secondary 
endpoint is statistically significant at a two-sided 0.05 level, the second key secondary endpoint 
(change in pruritus through week 52) will be tested at the same level. If the second key secondary 
endpoint is statistically significant at a two-sided 0.05 level, the third key secondary endpoint (change 
in pruritus through week 24) will be tested at the same level. 
LTE period 
All the efficacy endpoints (apart from histology – if applicable - and PK) considered for the DB period 
will be summarized using descriptive statistics by DB treatment group and overall on both ITT and 
PP sets. 
Safety analysis: 
Descriptive statistics will be provided on the SS according to the treatment groups and an overall 
summary will be produced. In addition, for AEs, exposure adjusted incidence rates (EAIR) will be 
compared between treatment groups presenting estimates with their confidence intervals (CIs). No 
formal significance testing is planned. Safety analyses will be performed for both DB treatment period 
and LTE period.  
Pharmacokinetic analysis: 
The PK analysis will be performed on the PKS using a PK pop model approach. 
PK parameters of elafibranor and GFT1007 will be calculated at steady state and summarized by 
geometric mean, SD, coefficient of variation, minimum and maximum, and median. 

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Exploratory analysis (related to histological assessments): 
Descriptive statistics on the histological scores and the non invasive markers of fibrosis (liver 
stiffness, ELF test and ProC3) will be provided by DB treatment groups and overall in the 
Exploratory (Histological) set. 
For assessing the correlation between the histological fibrosis endpoints (Nakanuma and Ishak 
scores) and the non invasive markers of fibrosis, the correlation coefficients and their CIs will be 
estimated depending on the nature and distribution of the endpoints considered.   

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g. 
Patient Global Impression of Severity (PGIS) will be collected at SV1 only during the screening period 
h. 
For patients who have consented to have liver biopsy samples collected, Liver biopsy at inclusion to be done at any SV  preferably in patients already confirmed as eligible and if at all possible 
2 to 4 weeks prior to randomization. LB at week 52 can be performed with a tolerance of +/- 2 weeks around the planned visit V6. 
i. 
PK assessment will include the following timepoints: predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h 
j. 
Until the last patient in the study completes his/her V5, patients between V6 and V8, will complete LVDB according to Table 1 General Assessment Schedule. After the last patient in the study 
completes his/her V5, patients between V6 and V8, will complete LVDB at the next scheduled visit (either V7 or V8). LVDB will replace V7 or V8. The same procedures as for V8 will be 
performed for LVDB (except US exam). For patients who have not yet had V6 at the time the last patient completes his/her V5, LVDB will be scheduled at the latest 13 weeks after the date 
on which V5 was completed for the last patient. For those patients, LVDB will coincide with V6, and patients will complete V6 and associated procedures to facilitate transition to the open-
label elafibranor treatment phase in the long-term extension study, in a timely manner.   . 
k. 
Safety contact by phone call every alternating 26 weeks starting 13 weeks after V6 in the DB period and starting after LT2 during LTE to check AEs and concomitant medications 
l. 
If premature study drug discontinuation during DB period, end of treatment (EOT) DB Visit should be performed between 16 and 30 days after last drug intake, and patients will continue in 
the study until V8, or until the last completed V5 whichever occurs first. In case the EOT DB visit occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled 
visit. If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed between 16 and 30 days after last drug intake 
m. 
Drug dispensation will be done up to LT10. There will be no drug dispensation at LT11 

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TABLE OF CONTENTS 
STUDY CONTACTS ................................................................................................................ 4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................. 5 
LIST OF ABBREVIATIONS .................................................................................................... 12 
CLINICAL STUDY SYNOPSIS ................................................................................................ 16 
TABLE OF CONTENTS ......................................................................................................... 37 
1 
INTRODUCTION AND RATIONALE............................................................................... 42 
1.1. 
BACKGROUND AND RATIONALE FOR ELAFIBRANOR IN PRIMARY BILIARY CHOLANGITIS ..................42 
1.2. 
SUMMARY OF NON CLINICAL STUDIES ................................................................................44 
1.2.1. 
Nonclinical Pharmacology .......................................................................................44 
1.2.1.1. 
In Vitro Pharmacology ................................................................................................... 44 
1.2.1.1.1. 
Activity on Human and Murine PPAR isoforms ............................................................... 44 
1.2.1.1.2. 
Anti-fibrotic Activity ................................................................................................. 44 
1.2.1.2. 
In Vivo Pharmacology .................................................................................................... 44 
1.2.1.2.1. 
Rat Model of CCl4-induced Hepatic Fibrosis .................................................................. 44 
1.2.1.3. 
Safety Pharmacology ..................................................................................................... 44 
1.2.1.4. 
Absorption/distribution/metabolism/excretion Studies (ADME) ............................................... 44 
1.2.1.5. 
Toxicology .................................................................................................................. 45 
1.2.1.5.1. 
Mutagenicity and Genotoxicity .................................................................................... 45 
1.2.1.5.2. 
Acute Toxicity ......................................................................................................... 45 
1.2.1.5.3. 
Repeated Dose Toxicity Studies ................................................................................... 46 
1.2.1.5.4. 
Phototoxicity Studies ................................................................................................. 46 
1.3. 
CLINICAL STUDIES ..........................................................................................................46 
1.3.1. 
Phase 1 Program ...................................................................................................46 
1.3.2. 
Phase 2 Program ...................................................................................................46 
1.4. 
CONCLUSION .................................................................................................................47 
1.5. 
RATIONALE FOR STUDY POPULATION .................................................................................47 
1.6. 
JUSTIFICATION OF THE SELECTED DOSE ..............................................................................48 
2 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 49 
2.1. 
OBJECTIVES ...................................................................................................................49 
2.1.1. 
DB Period.............................................................................................................49 
2.1.1.1. 
Primary Objective ......................................................................................................... 49 
2.1.1.2. 
Key Secondary Objectives ............................................................................................... 49 
2.1.1.3. 
Secondary Objectives ..................................................................................................... 49 
2.1.1.4. 
Exploratory Objectives (related to histological assessements) .................................................. 49 
2.1.2. 
LTE Period ...........................................................................................................50 
2.2. 
ENDPOINTS ....................................................................................................................50 
2.2.1. 
DB Period.............................................................................................................50 
2.2.1.1. 
Primary Endpoint .......................................................................................................... 50 
2.2.1.2. 
Secondary Endpoints ...................................................................................................... 50 
2.2.1.3. 
Exploratory Endpoints .................................................................................................... 51 
2.2.2. 
LTE Period ...........................................................................................................52 
3 
STUDY DESIGN ............................................................................................................ 53 
3.1. 
NUMBER OF PATIENTS .....................................................................................................55 
3.2. 
TREATMENT GROUPS .......................................................................................................55 
3.3. 
DOSE ADJUSTMENT CRITERIA ...........................................................................................55 
3.4. 
DURATION OF STUDY PARTICIPATION .................................................................................55 
3.5. 
STUDY PERIODS AND SCHEDULE OF ASSESSMENTS ...............................................................55 
3.5.1. 
Screening Period ....................................................................................................56 
3.5.2. 
DB period (Week 0 to max Week 104) ........................................................................56 
3.5.3. 
LT period ..............................................................................................................57 
3.5.4. 
Safety Follow up ....................................................................................................58 
3.5.5. 
Optional Visits .......................................................................................................58 

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3.5.5.1. 
Retesting and/or additional screening visits ......................................................................... 58 
3.5.5.2. 
Unscheduled visits ......................................................................................................... 58 
3.5.6. 
Off-site study procedures in case of crisis situation .......................................................58 
4 
PATIENT SELECTION .................................................................................................. 59 
4.1 
INCLUSION CRITERIA .......................................................................................................59 
4.2 
EXCLUSION CRITERIA ......................................................................................................60 
5 
STUDY PROCEDURES .................................................................................................. 62 
5.1. 
SCREEN FAILURES...........................................................................................................62 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES ............................62 
5.2.1. 
Permanent discontinuation of study drug/withdrawal from study .....................................62 
5.2.2. 
Patients Lost to Follow-up .......................................................................................63 
5.2.3. 
Replacement ..........................................................................................................63 
5.2.4. 
Premature Discontinuation of the Study ......................................................................63 
6 
ASSESSMENTS ............................................................................................................. 64 
6.1. 
EFFICACY AND SAFETY ASSESSMENT .................................................................................64 
6.1.1. 
Biological assessment .............................................................................................64 
6.1.1.1. 
Laboratory Assessments ................................................................................................. 64 
6.1.1.2. 
Urinary Pregnancy Tests ................................................................................................. 65 
6.1.1.3. 
Serology ...................................................................................................................... 65 
6.1.1.4. 
Other Parameters ........................................................................................................... 65 
6.1.2. 
Constitution of biobank ...........................................................................................65 
6.1.3. 
Bone density by DEXA scanning ................................................................................65 
6.1.4. 
Histological assessment ...........................................................................................65 
6.1.4.1. 
Recommendations related to liver biopsy ............................................................................ 66 
6.1.4.2. 
Liver biopsy reading ...................................................................................................... 66 
6.1.5. 
Pharmacokinetic assessment ....................................................................................66 
6.1.5.1. 
Pharmacokinetic blood sampling timepoints ........................................................................ 67 
6.1.5.2. 
Pharmacokinetic blood handling procedures ........................................................................ 67 
6.1.5.3. 
Bioanalytical analysis ..................................................................................................... 67 
6.1.5.4. 
Description of pharmacokinetic evaluation parameters ........................................................... 67 
6.1.6. 
Liver stiffness by transient elastography (FibroScan®) ...................................................68 
6.1.7. 
Patient Reported Outcomes Questionnaires .................................................................68 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING .........................................69 
6.2.1. 
Physical Examination..............................................................................................69 
6.2.2. 
Vital Signs and Weight ............................................................................................69 
6.2.3. 
12 Lead ECG .........................................................................................................70 
6.3. 
IMPORTANT SPECIFIC BIOLOGICAL CONSIDERATIONS AND PATIENT DISCONTINUATION RULES .......70 
6.3.1. 
Creatine Phosphokinase ..........................................................................................70 
6.3.2. 
Liver Function Monitoring .......................................................................................70 
6.3.2.1. 
Treatment discontinuation rule for elevated Aminotransferase (AT) values regardless of baseline 
values 
71 
6.3.2.2. 
Treatment discontinuation rules for elevated Aminotransferase (AT) values according to baseline 
values 
71 
6.3.2.2.1. 
Monitoring of patients with normal baseline AT values ..................................................... 71 
6.3.2.2.2. 
Monitoring of patients with abnormal baseline AT values .................................................. 72 
6.3.2.2.3. 
Monitoring of patients with abnormal TB baseline values .................................................. 72 
6.3.3. 
Auto-immune hepatitis monitoring .............................................................................72 
6.3.4. 
Acute Pancreatitis Monitoring ..................................................................................73 
6.3.4.1. 
Treatment discontinuation rule for suspected acute pancreatitis................................................ 73 
6.3.5. 
Monitoring of hepatocellular and bladder cancer .........................................................73 
6.3.5.1. 
Liver monitoring ........................................................................................................... 73 
6.3.5.2. 
Bladder & urinary tract monitoring .................................................................................... 73 
6.3.6. 
Safety Review ........................................................................................................73 
6.3.7. 
Clinical event committee ..........................................................................................73 
6.4. 
GUIDANCE FOR INVESTIGATORS ........................................................................................74 

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6.4.1. 
Summary of safety data ...........................................................................................74 
6.4.2. 
Benefit/risk assessment ............................................................................................75 
7 
TREATMENTS .............................................................................................................. 76 
7.1. 
DESCRIPTION OF STUDY MEDICATIONS ...............................................................................76 
7.2. 
PACKAGING AND LABELING .............................................................................................76 
7.2.1. 
Packaging .............................................................................................................76 
7.2.2. 
Labeling ...............................................................................................................76 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO ............................................76 
7.4. 
METHOD OF ASSIGNING PATIENT TO TREATMENT GROUP .......................................................77 
7.5. 
STORAGE CONDITIONS .....................................................................................................77 
7.6. 
DISPENSING OF TREATMENT .............................................................................................77 
7.7. 
TREATMENT REPLACEMENT ..............................................................................................77 
7.8. 
PROCEDURE FOR BLINDING ..............................................................................................77 
7.9. 
PROCEDURE FOR UNBLINDING ...........................................................................................78 
7.10. 
STUDY DRUG COMPLIANCE ..............................................................................................78 
7.11. 
TREATMENT ACCOUNTABILITY, RETRIEVAL AND DESTRUCTION ..............................................78 
7.12. 
OTHER MEDICATION .......................................................................................................79 
7.12.1. 
Handling of Concomitant Medication .........................................................................79 
7.12.2. 
Non-permitted Medication .......................................................................................79 
7.12.3. 
Permitted Medication Under Conditions .....................................................................79 
7.12.4. 
Permitted Medication ..............................................................................................79 
8 
ADVERSE EVENT AND TOXICITY MANAGEMENT ....................................................... 80 
8.1. 
DEFINITIONS ..................................................................................................................80 
8.1.1. 
Adverse Events (AEs) ..............................................................................................80 
8.1.2. 
Adverse events of special interest (AESIs) ...................................................................81 
8.1.3. 
Serious Adverse Event .............................................................................................81 
8.1.4. 
Clarification on Serious Adverse Events .....................................................................82 
8.1.5. 
Adverse Drug Reaction ............................................................................................82 
8.1.6. 
Unexpected Adverse Event .......................................................................................82 
8.2. 
ASSESSMENTS ................................................................................................................83 
8.2.1. 
Intensity Assessment ...............................................................................................83 
8.2.2. 
Relation to the Study Treatment ................................................................................83 
8.2.3. 
Action Taken and Outcome ......................................................................................83 
8.3. 
REPORTING ...................................................................................................................84 
8.3.1. 
Reporting an AE ....................................................................................................84 
8.3.2. 
Reporting a SAE or an AESI .....................................................................................84 
8.3.3. 
Follow-up .............................................................................................................85 
8.4. 
POST STUDY REPORTING REQUIREMENTS ............................................................................85 
8.5. 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES OR SAES 85 
8.6. 
SPECIAL SITUATION REPORTS ............................................................................................86 
8.6.1. 
Pregnancy ............................................................................................................86 
8.6.2. 
Medication Error ...................................................................................................86 
8.6.3. 
Misuse .................................................................................................................86 
8.6.4. 
Overdose ..............................................................................................................86 
8.6.5. 
Abuse ...................................................................................................................87 
9 
STATISTICAL METHODS AND DATA ANALYSIS ........................................................... 88 
9.1. 
ESTIMANDS CONSIDERATIONS ...........................................................................................88 
9.2. 
RANDOMIZATION AND TREATMENT ASSIGNMENT .................................................................90 
9.3. 
ENDPOINTS ....................................................................................................................90 
9.3.1. 
Primary Endpoint ...................................................................................................90 
9.3.2. 
Secondary Endpoints ..............................................................................................90 
9.3.3. 
Exploratory Endpoints (related to histological assessments) ...........................................92 
9.4. 
ANALYSIS SETS ..............................................................................................................92 

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9.5. 
ANALYSIS OF PRIMARY ENDPOINT .....................................................................................93 
9.6. 
OTHER STATISTICAL ANALYSIS .........................................................................................94 
9.6.1. 
Key secondary endpoints .........................................................................................94 
9.6.2. 
Other secondary endpoints .......................................................................................94 
9.6.3. 
Subgroup analyses ..................................................................................................95 
9.7. 
STRATEGIES TO CONTROL TYPE I ERROR .............................................................................95 
9.8. 
SAMPLE SIZE CALCULATION .............................................................................................96 
9.8.1. 
Reduction in ALP and TB .........................................................................................96 
9.8.2. 
Normalization in ALP .............................................................................................96 
9.9. 
SAFETY ANALYSIS ..........................................................................................................96 
9.10. 
EXPLORATORY ANALYSIS (RELATED TO HISTOLOGICAL ASSESSEMENTS) ....................................97 
10 
DATA HANDLING AND RECORD KEEPING ................................................................... 98 
10.1. 
DATA PROTECTION ..........................................................................................................98 
10.2. 
CASE REPORT FORM AND SOURCE DOCUMENTS ...................................................................98 
10.3. 
RETENTION OF RECORDS..................................................................................................99 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 100 
11.1. 
QUALITY CONTROL & MONITORING PROCEDURES ............................................................... 100 
11.2. 
ETHICAL PRINCIPLES ..................................................................................................... 100 
11.3. 
QUALITY ASSURANCE .................................................................................................... 101 
12 
ETHICS AND REGULATORY ...................................................................................... 102 
12.1. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ....................................... 102 
12.2. 
COMPETENT AUTHORITY ................................................................................................ 102 
12.3. 
PATIENT INFORMATION AND CONSENT.............................................................................. 102 
12.4. 
PATIENT CONFIDENTIALITY ............................................................................................. 103 
12.5. 
DEFINITION OF THE END OF THE RESEARCH ...................................................................... 104 
13 
FINANCING AND INSURANCE .................................................................................... 105 
13.1. 
FINANCIAL ISSUES ........................................................................................................ 105 
13.2. 
INSURANCE AND PATIENT INJURY .................................................................................... 105 
14 
STUDY RESULTS AND PUBLICATION POLICY ........................................................... 106 
14.1. 
STUDY REPORT ............................................................................................................ 106 
14.2. 
CONFIDENTIALITY AND OWNERSHIP OF DATA, USE OF THE STUDY RESULTS AND PUBLICATION .. 106 
15 
REFERENCES LIST .................................................................................................... 108 
16 
APPENDICES: ............................................................................................................. 110 
16.1. 
APPENDIX 1: ALCOHOL COMPARISON TABLE ...................................................................... 110 
16.2. 
APPENDIX 2: PERMITTED/NON-PERMITTED MEDICATION ...................................................... 111 
16.3. 
APPENDIX 3: SAMPLE PATIENT REPORTED OUTCOME QUESTIONNAIRES: .................................. 113 
16.3.1. 
PBC-40 .............................................................................................................. 113 
16.3.2. 
Epworth Sleepiness Scale (ESS) .............................................................................. 117 
16.3.3. 
5-D Itch Scale ...................................................................................................... 118 
16.3.4. 
PROMIS Fatigue Short Form 7a ............................................................................. 119 
16.3.5. 
The Patient Global Impression of Change (PGIC) ...................................................... 120 
16.3.6. 
The Patient Global Impression of Severity (PGIS) ...................................................... 121 
16.3.7. 
PBC Worst Itch NRS ............................................................................................. 122 
16.3.8. 
EuroQoL EQ-5D-5L ............................................................................................. 123 

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LIST OF TABLES 
Table 1: Study General Assessment Schedule ................................................................................................ 28 
Table 2: Study Biological Assessment Schedule .............................................................................................. 32 
Table 3: Schedule of Patient Reported Outcomes (PROs) Questionnaires .......................................................... 36 
 
LIST OF FIGURES 
Figure 1: Hazard Ratio for LT or Death (95% CI) vs. Bilirubin (×ULN) ........................................................... 48 
 
LIST OF SCHEMA 
Schema 1: GFT505B-319-1 Study Design ...................................................................................................... 16 
Schema 2: GFT505B-319-1 Study Design ...................................................................................................... 54 
 
 

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1 
INTRODUCTION AND RATIONALE 
Elafibranor has been developed by Genfit for the treatment of PBC. In December 2021, Genfit and IPSEN 
(“the partner”) entered into an exclusive licensing agreement for elafibranor, which gives the partner, 
the exclusive worldwide license for the future development of elafibranor in PBC, with the exception of 
China, Taiwan, Hong-Kong and Macau. The transfer of sponsorship from Genfit to IPSEN took place on 
8th August 2023, within approximately 30 days of top line results for the double-blind portion of the 
study (part A). 
1.1. 
BACKGROUND 
AND 
RATIONALE 
FOR 
ELAFIBRANOR 
IN 
PRIMARY 
BILIARY 
CHOLANGITIS 
Characterization of the disease 
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 
[5, 6]. 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 [7]. 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 [8]. 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 [6]. 
 
. Patients with PBC progress at varying rates, some experiencing liver decompensation over a period of 
several years while others over decades [9, 10]. PBC is one of the leading indications for liver 
transplantation. Despite its rarity, PBC remains an important cause of morbidity in the Western world. 
PBC has also been identified as an important risk factor for hepatocellular carcinoma [11]. 
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 ALP levels, a hallmark of 
the disease. Antimitochondrial antibody and IgM are specific immunological hallmarks of PBC, and 
antimitochondrial antibody is a diagnostic marker of the disease in approximately 90% of patients [12]. 
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) [13-15]. 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 [15]. 
As PBC advances, the transaminases ALT and AST may also be elevated due to hepatocellular damage 
secondary to cholestasis. While GGT lacks specificity, elevation of this enzyme in the presence of 
elevated ALP is confirmatory of a cholestatic condition such as PBC [16]. 

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The most common symptoms of PBC are fatigue and pruritus [17]. The mechanisms underlying these 
symptoms are not well elucidated and neither correlates with disease stage or clinical outcomes. 
Current Treatment Options 
UDCA, an epimer of the primary human bile acid UDCA, 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 [18]. 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 [19] and the European Association for the Study 
of the Liver (EASL) [20]. While UDCA has had a marked impact on clinical outcomes in PBC, a large 
proportion of patients have an inadequate response. It is estimated [11] that up to 40% of UDCA-
treated patients have a suboptimal response to UDCA. Lammers et al. found that ALP remains elevated 
in up to 70% of patients who are currently being treated or are intolerant to UDCA [15]. Such patients 
remain at risk of disease progression and longer term adverse clinical outcomes. 
Ocaliva (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 achieving a 
primary endpoint. The primary endpoint was defined as a composite endpoint of an ALP level of less 
than 1.67 times the ULN range, with a reduction of at least 15% from baseline, and a TB level at or 
below the ULN range at 12 months. On a background of standard of care, the rate of the primary 
endpoint was higher in the 5-10 mg group (46%) and in the 10 mg group (47%) compared to the 
placebo group at month 12 (p<0.001 for both comparisons). Pruritus was the most common AE across 
all groups, with a higher incidence reported in the 5-10 mg group (56%) and the 10 mg group (68%) 
than in the placebo group (38%) [4]. 
A 24-month, DB, placebo-controlled, phase 3 study of bezafibrate, a pan-peroxisome proliferator-
activated receptor (PPAR) agonist, demonstrated efficacy in patients who had an inadequate response 
to UDCA. In this study the primary outcome was the percentage of patients with a complete biochemical 
response, which was defined as normal serum levels of ALP, AST, ALT, total bilirumin and albumin, as 
well as a normal prothrombin index at 24 months. The result was the primary outcome occurred in 31% 
of the patients assigned to bezafibrate and in 0% assigned to placebo (p<0.001). Results regarding 
changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and ELF 
score, were consistent with the results of the primary outcome [21]. 
Rationale for Evaluation of Elafibranor in PBC 
Elafibranor is being developed by Ipsen for the treatment of PBC, based on its pharmacological 
properties as a PPAR/δ agonist. Activation of PPAR 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. PPAR and PPARδ receptor activation also has anti-inflammatory effects by acting on different 
pathways of inflammation (nuclear factor kappa B [NF-κB] and B-cell lymphoma 6 [BCL6] pathways). 
Ligand-activated PPAR contributes to a range of actions, including cholesterol and bile acid 
homeostasis. PPAR primarily downregulates bile acid synthesis. PPAR 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. Fenofibrate 
may also ameliorate cholestatic liver disease through its transcriptional activation of multidrug resistance 
protein type 3 (MDR3) [22]. 

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1.2. 
SUMMARY OF NON CLINICAL STUDIES 
1.2.1. 
Nonclinical Pharmacology 
1.2.1.1. 
In Vitro Pharmacology 
1.2.1.1.1. 
Activity on Human and Murine PPAR isoforms 
In Gal4- PPAR reporter gene assays, elafibranor (GFT505) and its main metabolite GFT1007 are PPAR 
agonists with a similar selectivity profile on both the human and murine PPAR isoforms. Both (GFT505) 
and GFT1007 activate the PPAR subtype with a 5-fold selectivity over PPARδ. 
In human hepatocytes, elafibranor and GFT1007 induce the expression of mitochondrial genes 
(pyruvate dehydrogenase kinase [PDK]4, carnitine palmitoyltransferase [CPT]1a) but not peroxisomal 
PPAR target genes (acylCoA-oxidase [ACOX]1, enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase 
[EHHADH]), likely via PPARδ activation. 
In stimulated human monocytes, elafibranor decreases the secretion of inflammatory markers 
(monocyte chemotactic protein (MCP)-1 and tumor necrosis factor [TNF-]) through combined PPAR 
and PPARδ activation and parallel PPAR-independent mechanisms. 
1.2.1.1.2. 
Anti-fibrotic Activity 
Anti-fibrotic properties of (GFT505) were demonstrated in primary human hepatic stellate cells (hHSC). 
(GFT505) inhibits hHSC proliferation induced by either fetal calf serum or platelet-derived growth factor 
(PDGF)-BB. Moreover, (GFT505) specifically inhibited PDGF-BB-induced 
PDGF receptor 
β 
phosphorylation in vitro. (GFT505) also inhibited hHSC activation (gene expression of fibrosis markers: 
α-smooth muscle actin [αSMA], collagen [Col] 1α1 and Col4α1) induced by TGF β1. 
 
1.2.1.2. 
In Vivo Pharmacology 
1.2.1.2.1. 
Rat Model of CCl4-induced Hepatic Fibrosis 
The liver-protective effects of (GFT505) have also been demonstrated in a rat model of carbon 
tetrachloride (CCl4)-induced hepatic fibrosis. When administered concomitantly with CCl4, (GFT505) 
totally prevented the development of liver fibrosis evaluated by macroscopic and microscopic 
examination. In addition, (GFT505) significantly reduced CCl4-induced macro- and micro- steatosis and 
liver inflammation. (GFT505) treatment prevented the CCl4-induced increase in liver expression of genes 
involved in the inflammatory ( [IL]-1β, RANTES) and pro-fibrotic (collagens [Col1α1, Col1α2], TGFβ1, 
TIMP-2, αSMA) response. 
1.2.1.3. 
Safety Pharmacology 
Any potential effects on the cardiovascular, respiratory, and central nervous system have been assessed 
and no safety issue was identified. 
1.2.1.4. 
Absorption/distribution/metabolism/excretion Studies (ADME) 
In animal studies, elafibranor (GFT505) was well and rapidly absorbed although absolute bioavailability 
was moderate (about 20% to 40%). (GFT505) is extensively metabolized and the activity is mainly 

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carried by the active metabolite GFT1007. In rat and dog, maximal plasma concentrations and exposure 
for both (GFT505) and GFT1007 linearly increase with the dose after single or repeated administrations. 
(GFT505) 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, (GFT505) and/or its metabolites are rapidly excreted 
into the bile and undergo an extensive entero-hepatic cycle giving support for liver targeting of (GFT505) 
and/or GFT1007. The distribution study in the rat supports the liver targeting of (GFT505) and/or its 
metabolites. 
In vitro, (GFT505) 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 (DDI) 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 PK interaction of 
(GFT505) 120 mg administered for 14 days alone or with a single administration of warfarin. This study 
demonstrated that (GFT505) administration did not affect the PK profile of warfarin (R-warfarin and 
S-warfarin). A protein binding study showed that (GFT505) and GFT1007 were highly bound to human 
serum albumin. The risk of DDI due to albumin binding should be limited since this binding is not 
saturable. 
In vitro studies have been performed to determine whether GFT505 and its principal metabolite 
GFT1007 are substrates and/or inhibitors of major drug transporters, in order to assess the potential 
for DDI. Based on the results of the OATP1B3 (organic anion transporting polypeptide 1B3) transporter 
inhibition assay, 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 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%). 
1.2.1.5. 
Toxicology 
1.2.1.5.1. 
Mutagenicity and Genotoxicity 
The toxicology program performed according to the International Conference on Harmonisation (ICH) 
guidelines demonstrates that (GFT505) has no genotoxic or mutagenicity potential. 
1.2.1.5.2. 
Acute Toxicity 
According to acute toxicity study results, it can be concluded that (GFT505) 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. 

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1.2.1.5.3. 
Repeated Dose Toxicity Studies 
The safety of (GFT505) has been assessed in multiple preclinical toxicology studies with repeated-dose 
oral administration for up to 6 months in rats and 12 months in monkeys. Moreover, two-year 
repeated-dose carcinogenicity studies in mice and rats have been completed. 
The only consistent safety concern raised by these studies is the expected PPAR-associated 
hepatomegaly, hepatocellular hypertrophy, and liver carcinoma in rodent species (mice and rats). 
However, it is well known that, compared to nonhuman primates and humans, rodents are highly 
sensitive to PPAR agonist induced peroxisome proliferation and associated liver side effects. Thus, 
available information on this class of drug which includes marketed fibrates together with the lack of 
any liver side effects in monkeys treated with high doses of (GFT505) for 1 year support the non-
relevance to human [23]. Overall, these studies did not reveal any other safety issues up to the highest 
doses tested. Notably, (GFT505) did not have any of the known PPAR-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 (GFT505). 
1.2.1.5.4. 
Phototoxicity Studies 
The phototoxic potential of elafibranor has been assessed by the in vitro 3T3 Neutral Red Uptake (NRU) 
phototoxicity test and the UV-Local Lymph Node Assay (UV-LLNA) test in mice. 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 (GFT505). Although a very 
conservative No Observed Adverse 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 GFT505, and absence of phototoxicity signal in the clinical studies. 
Additional information can be found in the Investigator’s Brochure (IB). 
 
1.3. 
CLINICAL STUDIES 
1.3.1. 
Phase 1 Program 
A Phase 1 program to assess the safety and the tolerability, as well as the PK profile, of elafibranor 
currently comprises 19 completed clinical pharmacology studies. At least 732 healthy and lean subjects, 
90 overweight or obese but otherwise healthy subjects, 59 subjects with type 2 diabetes, 13 with renal 
impairment (ESRD) and 20 with hepatic impairment (Child-Pugh class A, B or C). Elafibranor daily doses 
ranged between 5 mg and 360 mg, with a maximum treatment duration of 18 days. 
Additional information can be found in the IB. 
1.3.2. 
Phase 2 Program 
One phase 2 study with elafibranor was completed in PBC patients. Study GFT-505B-216-1 was a 12-
week, DB, randomized, parallel group, placebo-controlled, proof-of-concept study in PBC. A total of 45 
adult patients were randomized to one of 3 treatments arms in a 1:1:1 ratio: elafibranor 80 mg, 
elafibranor 120 mg, or placebo. In both elafibranor-treated groups, a significant decrease in mean ALP 
was achieved: -48% for the 80 mg dose and -41% for 120 mg dose, compared to a mean 3% increase 
in ALP for subjects receiving placebo. This resulted in a highly significant treatment effect versus 

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placebo: -52% (95% CI: [-62.5;-41.5]) (p<0.001) for 80 mg and -43.9% (95% CI: [-55.7;-32.1]) (p< 
0.001) for 120 mg elafibranor. There was no apparent difference in the magnitude of improvement 
between the 2 elafibranor doses suggesting a plateau of the dose exposure-response. The effect was 
observed from the first visit following baseline (Visit 2 [Week 2]) and was maintained and reinforced up 
to the end of the active treatment period. A composite endpoint composed of ALP <1.67xULN and ALP 
decrease >15% and TB <ULN, was achieved in 66.7% subjects at 80 mg and 78.6% of subjects at the 
120 mg elafibranor dose (p= 0.002 and p< 0.001, respectively) as compared to 6.7% subjects on 
placebo. 
Additional information can be found in the IB. 
1.4. 
CONCLUSION 
In summary, elafibranor may provide an effective therapeutic option for patients with PBC who are 
inadequately responding to or unable to tolerate UDCA. As a result, elafibranor will be further evaluated 
in this larger Phase 3 study with an open-label extension. 
1.5. 
RATIONALE FOR STUDY POPULATION 
Partial or suboptimal responders constitute up to 40% of UDCA-treated PBC patients [11]. This group 
of patients along with patients intolerant to UCDA treatment will be randomized in this study. 
This study targets patients with mild and moderately advanced disease and excludes patients with 
advanced cirrhosis. ALP reduction is not a good predictive marker of long term benefit in the advanced 
disease population [15]. Patients with moderately advanced disease are identified per Rotterdam Criteria 
(TB > ULN or Albumin < LLN), liver stiffness measurement by Fibroscan [EASL Clinical Practice 
Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis –2021 update, J 
Hep 2021], or histology among those who undergo liver biopsy. Patients with cirrhosis will be identified 
by elastography [24] or histology among those who undergo liver biopsy. 
In addition, a recent publication has shown that in UDCA-treated and untreated patients with TB levels 
≤1×ULN at baseline or 1 year, the TB threshold with the highest ability to predict LT or death at 1 
year was 0.6×ULN. The risk for LT or death was stable below TB levels of 0.6×ULN and yet increased 
beyond this threshold [25] and Figure 1. 
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term clinical outcomes or 
moderate disease stage, approximately 10% of randomized patients will be moderately advanced per 
Rotterdam Criteria. Patients will also be categorized as early or advanced disease stage based on liver 
stiffness measurement at the baseline Fibroscan examination (LSM<=10 kPa or LSM >10 kPa), and 
based on histology (absent or mild fibrosis vs. presence of bridging fibrosis or cirrhosis) among those 
who undergo liver biopsy [EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver 
disease severity and prognosis –2021 update, J Hep 2021].  Additionally, approximately 20% will have 
a TB > 0.6 x ULN (patients at risk of progression). 

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Figure 1: Hazard Ratio for LT or Death (95% CI) vs. Bilirubin (×ULN) 
 
 
 
1.6. 
JUSTIFICATION OF THE SELECTED DOSE 
There was no apparent difference in the magnitude of improvement of cholestatic paramaters (ALP, 
GGT and 5’ NT) between the two elafibranor doses (80 and 120 mg) in Study GFT-505B-216-1 
suggesting a plateau of the dose-exposure-response. In addition, both doses were generally well-
tolerated. As a result, elafibranor 80 mg was selected for this study. 

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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
OBJECTIVES 
2.1.1. 
DB Period 
2.1.1.1. 
Primary Objective 
To evaluate the effect of elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint 
over 52 weeks of treatment compared to placebo. 
2.1.1.2. 
Key Secondary Objectives 
To evaluate the effect of elafibranor (80mg/day) over 52 weeks of treatment compared to placebo on:  
- 
Normalization of ALP 
- 
Pruritus based on change from baseline through week 52 in PBC Worst Itch NRS in patients 
with baseline PBC Worst Itch NRS score ≥4  
- 
Pruritus based on change from baseline through week 24 in PBC Worst Itch NRS in patients 
with baseline PBC Worst Itch NRS score ≥4 
2.1.1.3. 
Secondary Objectives 
To evaluate the effect of elafibranor (80 mg/day) over 52 weeks of treatment compared to placebo on: 
a) Hepatobiliary injury and liver function markers 
b) Inflammation and hepatic fibrosis 
c) Lipid parameters 
d) Bile acids 
e) Pruritus Patient Reported Outcomes (PROs) 
f) 
Patient-reported Fatigue  
g) Patient-reported Sleep  
h) HRQoL 
i) 
Health utility 
j) 
Bone markers and bone density 
k) Safety and tolerability 
To determine the PK parameters of elafibranor and its active metabolite GFT1007, at steady state 
following daily oral administration at 80 mg) in PBC patients.Of note, and in order to further collect 
safety and clinical outcomes data in a DB manner, placebo controlled treatment will be maintained until 
the last completed week 52 visitor until a maximum of 104 weeks, whichever occurs first. When this 
time point is reached, every patient will be switched to open-label Elafibranor 80 mg. 
2.1.1.4. 
Exploratory Objectives (related to histological assessements) 
For the patients having consented to participate: 
1) To constitute a biobank for discovery and validation of biomarkers associated with PBC 
2) Based on histology: 
a) To assist the interpretation of efficacy and safety results of elafibranor 
b) To explore the correlation of fibrosis scores with non-invasive markers of fibrosis (liver 
stiffness, ELF test and ProC3) 
 

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2.1.2. 
LTE Period 
To evaluate the effect of elafibranor (80 mg/day) during the LTE period on: 
a) Safety and tolerability 
b) Maintenance of efficacy from the DB period 
2.2. 
ENDPOINTS 
2.2.1. 
DB Period 
2.2.1.1. 
Primary Endpoint 
Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 
15%. 
2.2.1.2. 
Secondary Endpoints 
Key Secondary Endpoints 
1) Response to treatment based on ALP normalization at week 52. 
2) Change in pruritus from baseline through week 52 based on PBC Worst Itch NRS in patients with 
baseline PBC Worst Itch NRS score ≥4. 
3) Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with 
baseline PBC Worst Itch NRS score ≥4  
Other Secondary Endpoints 
1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks 
2) ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52 
3) Response to treatment at week 52 according to: 
a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN 
b) ALP < 3 x ULN, AST <2x ULN and TB < 1 mg/dL (Paris I) 
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5x ULN and TB ≤ ULN (Paris II) 
d) TB response rate of 15% change 
e) Normalization of abnormal TB and/or albumin (Rotterdam) 
f) 
TB ≤ 0.6 x ULN 
g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1] 
h) No worsening of TB defined as level of TB at week 52 < ULN or no increase from baseline of 
more than 0.1XULN at week 52 
i) 
Complete biochemical response defined as normal ALP; TB; AST; ALT; albumin; and INR 
4) PBC risk scores at week 52: UK PBC score [2] and GLOBE score [3]  
5) Response based on the normalization of bilirubin at week 52 
6) Response based on the normalization of albumin at week 52 
7) Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST, 
ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic) 

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8) Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP, 
fibrinogen, haptoglobin and TNF- 
9) Change from baseline to week 52 in immune response as measured by IgG and IgM 
10) Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis as 
measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and liver 
stiffness measured by TE (continuous) 
11) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, calculated 
VLDL-C and triglycerides (TG) 
12) Change from baseline to week 52 in FPG 
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured 
by bile acids, C4 and FGF-19 
14) Proportion of responders in PBC Worst Itch NRS  according to clinically meaningful change; at 
least 30% reduction; and one point, two points or three points decrease in score from baseline 
through week 52 and through week 24 in patients with a baseline NRS score ≥ 4 
15) Proportion of patients with no worsening of pruritus from baseline through week 52 and through 
week 24 as measured by the PBC Worst Itch NRS  
16) Change from baseline to week 52 in 5D-Itch 
17) Change from baseline to week 52 in PROMIS Fatigue Short Form 7a 
18) Change from baseline to week 52 in ESS 
19) Change from baseline to week 52 in PBC-40 
20) Change from baseline to week 52 in health utility as measured by the EQ-5D-5L 
21) Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density 
(hip and lumbar) assessed by DEXA scanning 
22) Onset of clinical outcomes described as a composite endpoint composed of: 
a) MELD-Na >14 for patients with baseline MELD-Na <12 
b) Liver transplant 
c) Uncontrolled ascites requiring treatment 
d) Hospitalization for new onset or recurrence of any of the following: 
i) 
variceal bleed 
ii) hepatic encephalopathy defined as West-Haven score of 2 or more 
iii) spontaneous bacterial peritonitis 
e) Death 
23) Safety and tolerability as assessed by: 
a) SAE, AE, AESI, physical examination, vital signs, medical history, ECG 
b) Chemistry and hematology 
c) Liver markers 
d) Renal biomarkers (including urinalysis) 
e) Other biochemical safety markers 
24) PK assessments by GFT505 and GF1007 concentrations measurement in plasma 
2.2.1.3. 
Exploratory Endpoints 
Exploratory endpoints associated with Histological assessment (for patients who have consented to 
having liver biopsy) 

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1) Change from baseline in the histological scores 
a) Fibrosis stage according to Nakanuma scoring  
b) Bile duct loss scores 
c) Cholangitis activity 
d) Interface Hepatitis activity 
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct loss score) 
f) 
Other exploratory scores (Fibrosis according to Ishak scoring, portal inflammation, ductular 
reaction, cholestasis, concentric periductal fibrosis) 
2) Correlation of Fibrosis scores with non-invasive markers of fibrosis (Liver stiffness, ELF test and 
ProC3) 
 
2.2.2. 
LTE Period 
Additionally, apart from histology (if applicable) and PK assessments, the same endpoints as for the DB 
period will be collected over the LTE period to assess the maintenance of efficacy and safety of the 
treatment. The endpoints will be described using descriptive statistics by DB treatment group and overall 
on both ITT and PP sets. 

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3 
STUDY DESIGN 
This is a phase 3, randomized, DB, placebo-controlled, parallel group study followed by an open-label 
LTE that evaluates the efficacy and safety of elafibranor in patients with PBC and inadequate response 
or intolerance to UDCA. 
In the DB period, approximately 150 patients will be randomized in a 2:1 ratio to receive elafibranor 80 
mg or placebo, once daily, for maximum 104 weeks or until the last completed week 52 visit (V6), 
whichever happens first. Placebo control will be maintained after week 52 notably to further collect 
safety and clinical outcome data in a DB manner. At the end of the DB period, all patients will receive 
elafibranor 80 mg, once daily, for up to 5 years or until the patient’s total treatment duration is 6 years, 
whichever occurs first. When applicable, patients should continue their pre-study dose of UDCA 
throughout the study participation. 
 

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Schema 2: GFT505B-319-1 Study Design 
 
 
Footnotes:  
a. If receiving UDCA at randomization, continue throughout study participation 
b. The Variable DB duration is an additional 52 weeks after end of Common DB (W104) or until the last completed V6 (W52), whichever occurs first 
c. The LTE duration is 5 years after end of the DB period or until the patient’s total treatment duration is 6 years, whichever occurs first 
d. Safety follow-up 4 weeks after last dose of study drug 
 

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3.1. 
NUMBER OF PATIENTS 
The study is projected to randomize approximately 150 patients, including approximately 15 patients 
(10% of the total randomized patients) with a TB above ULN or albumin below LLN and approximately 
30 patients (20% of the total randomized patients) with a TB above 0.6 x ULN. 
3.2. 
TREATMENT GROUPS 
The treatment groups will be allocated, in a 2:1 ratio, to receive either elafibranor 80 mg or placebo 
during the DB period. 
3.3. 
DOSE ADJUSTMENT CRITERIA 
N/A 
3.4. 
DURATION OF STUDY PARTICIPATION 
Up to approximately 6 years, or 328 weeks (2 to 12 weeks for the screening period, 52 to 104 weeks 
for the DB period, 208 to 260 weeks for the LTE period, and 4 weeks for safety follow-up). The full 
treatment period for each patient will last 312 weeks, with a variable number of weeks in the DB Period 
and in the LTE Period depending the time point of the visit V8 or LVDB completed. 
3.5. 
STUDY PERIODS AND SCHEDULE OF ASSESSMENTS 
The study will be comprised of 3 periods: a screening period, a DB period and a LTE period. 
A schedule of assessments by visit is presented in Table 1 and Table 2. 
 

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3.5.1. 
Screening Period 
As a first step,  patients will be asked if they agree to participate in the study and sign the Informed 
Consent Form (ICF). Each patient who has signed the ICF will perform procedures listed on Table 1 and 
Table 2. Screening visits (SV1, SV2 or SV3) should be performed within 2 to 12 weeks of randomization. 
At SV1, preliminary eligibility criteria will be reviewed. 
For the purpose of establishing relevant baseline chemistries for suspected DILI, repeated measures of 
AST, ALT and TB will be collected (see Laboratory Manual) ONLY if the first measure (M1) collected at 
SV1 is > ULN. M1 and another value either a historical value (M0), collected at least 4 weeks and up to 
12 weeks apart before SV1, or a second measure (M2) will be collected at SV2 (4 to 6 weeks after SV1). 
This applies to only the analyte above ULN. 
• 
If variability between M1 and either M0 or M2 is ≤ 40% the patient is eligible 
• 
If variability between M1 and either M0 or M2 is > 40% a third measure (M3) will collected at 
SV3 (4 to 6 weeks after SV1 (if M0 compared) or SV2 (if M2 compared)): 
o 
If variability between M1 and M3 is ≤ 40% the patient is eligible 
o 
If variability between M1 and M3 is > 40% the patient is ineligible for the study 
To assess the ALP eligibility criterion, two ALP values will be required. One value is the M1 collected at 
SV1, and the other value is M0 collected at least 4 weeks and up to 12 weeks apart before SV1 or M2 
collected at SV2 (4 to 6 weeks after SV1). 
• 
If M1 is < 1.67 x ULN, the patient will be excluded and no further assessment will be performed 
• 
If M1 is ≥ 1.67 x ULN, and the mean of M1 and either M0 or M2 is ≥ 1.67 x ULN, and variability 
is ≤ 40% the patient is eligible 
• 
If M1 is ≥ 1.67 x ULN, and the mean of M1 and either M0 or M2 is < 1.67 x ULN or variability 
is > 40%, M3 collected at SV3 (4 to 6 weeks after SV1 (if M0 compared) or SV2 (if M2 
compared)) will be required: 
o 
If the mean of M1 and M3 is ≥ 1.67 x ULN and variability is ≤ 40%, the patient is 
eligible 
o 
If the mean of M1 and M3 is < 1.67 x ULN or variability is > 40%, the patient is ineligible 
for the study 
NOTE: M2 and M3 values for AST, ALT, TB and ALP can be obtained at local laboratory. Comparison 
between M1 and local value(s) will be done on normalized values according to ULN. 
For patients having consented to have liver biopsy samples collected and in absence of valid historical 
liver biopsy, the liver biopsy can be performed at any visits during the screening period, preferably in 
patients already confirmed as eligible and if at all possible 2 to 4 weeks prior to randomization. 
Screening is a minimum duration of 2 weeks to help ensure the stability of the PBC Worst Itch NRS daily 
scores for the calculation of the baseline score. 
In case of ineligibility, the patient should be contacted as soon as possible. 
3.5.2. 
DB period (Week 0 to max Week 104) 
At the Randomization visit 1 (week 0), all eligibility criteria will be reviewed for inclusion including lab 
assessments obtained during the screening period.  
Randomization in IXRS will be stratified based on central lab assessments obtained for ALP & TB at SV1, 
as well as on the mean PBC Worst Itch NRS Score over the 14 days preceding the visit 1. 

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At least 4 values of the PBC Worst Itch NRS during each of the 7-day intervals in the 14 days prior to 
randomization (V1), for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to 
randomization (V1) are required for randomizing the patients. In case this number is not achieved, the 
screening period may be extended in order to obtain the expected number of NRS values. 
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term clinical outcomes 
or moderate disease stage, approximately 10% of randomized patients will be moderately advanced 
per Rotterdam Criteria (TB> ULN or Albumin < LLN) and approximately 20% will have a TB > 0.6 x 
ULN (patients at risk of progression). Patients will also be categorized as early or advanced disease 
stage based on liver stiffness measurement at the baseline Fibroscan examination (LSM<=10 kPa or 
LSM >10 kPa), and based on histology (absent or mild fibrosis vs. presence of bridging fibrosis or 
cirrhosis) among those who undergo liver biopsy [EASL Clinical Practice Guidelines on non-invasive 
tests for evaluation of liver disease severity and prognosis –2021 update, J Hep 2021]. 
The DB period will last until the last completed week 52 (V6) visit or until a maximum of 104 weeks DB 
period, whatever happens first. 
During the DB period the patients will return to the site every 13 weeks (±2 weeks) from V1 up to V6 
(week 52) except for the V2 (4 weeks after V1) and if applicable post V6, every 26 weeks up to V8; 
Between V6 and V8, safety contacts will be performed by phone call between on site visits, every 
alternating 26 weeks (+/-14 days), to collect information related to AEs, concomitant medications, 
pregnancy, and study drug compliance. The first phone safety contact will start 13 weeks after V6 as 
applicable. 
Any patient completing V8 will be automatically switched to open-label LTE. The last V5 completed for 
all randomized patients will trigger the switch to open-label LTE for all patients still in DB. The switch 
will be operated either at V6 or at an additional onsite visit (LVDB). Until the last patient in the study 
completes his/her V5, patients between V6 and V8, will complete LVDB according to Table 1 General 
Assessment Schedule. After the last patient in the study completes his/her V5, patients between V6 and 
V8, will complete LVDB at the next scheduled visit (either V7 or V8). LVDB will replace V7 or V8. The 
same procedures as for V8 will be performed for LVDB (except US exam). For patients who have not 
yet had V6 at the time the last patient completes his/her V5, LVDB will be scheduled at the latest 13 
weeks after the date on which V5 was completed for the last patient. For those patients, LVDB will 
coincide with V6, and patients will complete V6 and associated procedures to facilitate transition to the 
open-label elafibranor treatment phase in the long-term extension study, in a timely manner.   
In case of premature study drug discontinuation prior to visit 8 during DB period, EOT DB visit should 
be performed between 16 and 30 days after last drug intake. The patients will continue in the study 
until V8, or until the last completed V5 whichever occurs first, and will complete all visit procedures 
except liver biopsy and PK (if not done prior to study drug discontinuation). In case the EOT DB visit 
occurs within the time window of the next scheduled visit, EOT DB visit replaces the scheduled visit. For 
any EOT patients, their EOS status will be registered in relevant study system(s) as applicable. 
Patients will be contacted at least 1 week before each onsite visit to be reminded of procedures and 
study drug return.  
The study scheduled assessments will be performed as per Table 1 and Table 2. 
3.5.3. 
LT period 
After the last DB visit, patients will continue to the LTE period (open label). During the LTE period, all 
patients will receive elafibranor 80 mg for up to 5 years after the DB period or until the patient’s total 
treatment duration is 6 years, whichever occurs first.  

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Apart from the first 2 visits in this LTE period which will occur at 13 weeks interval starting after the last 
visit in the double-blind period (V6, V7, V8), patients will return to the site every 26 weeks (+/-14 days) 
for procedures listed on Table 1 and Table 2, and safety contacts by phone call will be performed, every 
alternating 26 weeks (+/-14 days) after LT2, to collect information related to AEs, concomitant 
medications, pregnancy, and study drug compliance. The Investigator may subsequently decide to 
perform an unscheduled visit (see Section 3.5.5.2). 
If premature study drug discontinuation occurs during LTE period, an EOT LTE visit will be performed 
between 16 and 30 days after last drug intake. 
For any patients in the LTE, their EOS status will be registered in relevant study system(s) as applicable. 
3.5.4. 
Safety Follow up 
An EOT DB or EOT LTE visit will be performed between 16 to 30 days after the last drug intake for any 
subjects who received the study drug. The study procedures will be assessed as per the Table 1 and 
Table 2. 
3.5.5. 
Optional Visits 
3.5.5.1. 
Retesting and/or additional screening visits 
• 
If CPK value is >2xULN at SV1, it can be repeated within 1 to 2 weeks, but prior to V1 
If HCV Ab test is positive at SV1, a patient’s HCV infection status needs to confirmed by HCV RNA testing 
prior to V1Any other 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 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.). 
3.5.6. 
Off-site study procedures in case of crisis situation 
In cases of emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure patient 
safety and minimize risks to study integrity, certain study procedures may be completed remotely (e.g., 
not on-site) for patients already randomized in the study. Any temporary changes to study conduct will 
be defined based on a risk assessment specific to the crisis, and regulatory agencies and ethics 
committees will be informed in accordance with local laws and regulations.     
The temporary study conduct changes might include:  
• 
Study visits conducted with the patient via phone   
• 
Laboratory testing performed in the patient’s local lab 
• 
Study drug shipped from the site or supplier to the patient, or delivered by the site study staff 
to the patient 
 
Certain changes may be applied on a case-by-case basis depending on the investigator’s judgment. 
The investigator will confirm a patient's agreement before implementing any temporary study conduct 
changes. 
 

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4 
PATIENT SELECTION 
A patient will be eligible for the study only if all of the following criteria apply: 
4.1 INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for randomization into the study: 
1) Must have provided written informed consent and agree to comply with the study 
protocol  
2) Males or females age of 18 to 75 years inclusive at SV1 
3) PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic 
criteria: 
a. 
History of elevated ALP levels for ≥ 6 months prior to randomization (V1) 
b. 
Positive AMA titers (> 1:40 on immunofluorescence or M2 positive by ELISA or 
positive PBC-specific ANA  
c. 
Liver biopsy consistent with PBC 
4) ALP ≥ 1.67 x ULN (based on two values - see section 3.5.1) 
5) TB ≤ 2 x ULN 
To ensure inclusion of a relevant ratio of patients with substantial risk of long-term 
clinical outcomes or moderate disease stage, approximately 10% of randomized 
patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin < 
LLN) and approximately 20% will have a TB > 0.6 x ULN (patients at risk of 
progression) 
6) Must have at least 4 available values for PBC Worst Itch NRS during each of the 7 day 
intervals in the 14 days prior to randomization (V1), for a total of at least 8 values for 
PBC Worst Itch NRS in the last 14 days prior to randomization (V1) 
7) UDCA for at least 12 months (stable dose ≥ 3 months) prior to screening, or unable 
to tolerate UDCA treatment (no UDCA for ≥ 3 months) prior to screening (per country 
standard-of-care dosing) 
8) If on colchicine must be on a stable dose for ≥ 3 months prior to screening 
9) Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone 
or sertraline) must be on a stable dose for ≥ 3 months prior to screening 
10) Patients taking statins or ezetimibe must be on a stable dose for ≥ 2 months prior to 
screening 
11) Females participating in this study must be of non-child bearing potential or must be 
using highly effective contraception for the full duration of the study and for 1 month 
after the last drug intake: 
• 
Non-child bearing potential: Cessation of menses for at least 12 months due to 
ovarian failure or surgical sterilization such as bilateral oophorectomy, or 
hysterectomy  
• 
Highly effective contraception methods include:  
a. Combined 
(estrogen 
and 
progrestogen 
containing) 
hormaonal 
contraception associated with inhibition of ovulation, oral, intravaginal or 
transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation, oral, injectable or implantable 

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c. Intrauterine device (IUD) 
d. Intrauterine hormoine release system (IUS) 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence, if required by local IRB/IEC regulations and/or 
considered adequate by National laws (the reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and 
the preferred and usual lifestyle of the patient) 
12) For patients who consent to have liver biopsy samples collected, patients in whom it 
is safe and practical to proceed with a liver biopsy, and who agree to have: 
a. 1 liver biopsy during the Screening Period (if no historical biopsy within 6 months before 
screening is available) 
b. 1 liver biopsy after 52-weeks of treatment 
4.2 
EXCLUSION CRITERIA 
Patients presenting any of the following exclusion criteria will not be included in the study: 
1) History or presence of other concomitant liver disease including: 
a) Positive anti-HAV IgM antibodies or positive HBsAg or positive HCV RNA (tested for 
in case of known cured HCV infection or positive HCV Ab at screening) 
b) PSC 
c) ALD 
d) AIH or if treated for an overlap of PBC with AIH, or if there is suspicion and evidence 
of overlap AIH features, that cannot be explained alone by insufficient response to 
UDCA 
e) NASH 
f) 
Gilbert’s Syndrome (exclusion due to interpretability of bilirubin levels) 
g) Known history of alpha-1 antitrypsin deficiency 
2) Clinically significant hepatic decompensation, including: 
a) History of liver transplantation, current placement on a liver transplant list, current 
MELD-Na score ≥ 12 linked to hepatic impairment 
b) Patients with cirrhosis/portal hypertension complications, including known 
esophageal varices, ascites, history of variceal bleeds or related interventions (e.g., 
insertion of variceal bands or TIPS, and hepatic encephalopathy, history or presence 
of spontaneous bacterial peritonitis, hepatocellular carcinoma 
c) Hepatorenal syndrome (type I or II) 
3) Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s disease) 
or which may diminish life expectancy to < 2years, including known cancers 
4) Patient has a positive test for HIV Type 1 or 2 at screening, or patient is known to have 
tested positive for HIV 
5) Evidence of any other unstable or untreated clinically significant immunological, 
endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated 
by the investigator; other clinically significant medical conditions that are not well 
controlled  

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6) 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 screening visit (SV1) 
7) For female patients: known pregnancy, or has a positive serum pregnancy test, or 
lactating 
8) Administration of the following medications are prohibited as specified below: 
a) 2 months prior to screening: fibrates and glitazones 
b) 3 months prior to screening: OCA, azathioprine, cyclosporine, methotrexate, 
mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids 
(parenteral and oral chronic administration only); potentially hepatotoxic drugs 
(including α-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin) 
c) 12 months prior to screening: antibodies or immunotherapy directed against ILs or 
other cytokines or chemokines 
d) For patients with previous exposure to OCA, OCA should be discontinued 3 months 
prior to screening 
9) Patients who are currently participating in, plan to participate in, or have participated in 
an investigational drug study or medical device study containing active substance within 
30 days or five half-lives, whichever is longer, prior to screening; for patients with 
previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to 
screening 
10) Patients with previous exposure to elafibranor 
11) SV value ALT and/or AST > 5 x ULN 
12) For patients with AT or TB>ULN at SV1, variability of AT or TB > 40% (see section 3.5.1) 
13) SV value albumin<3.0 g/dl 
14) Severely advanced patients according to Rotterdam criteria (TB > ULN and albumin < 
LLN) 
15) SV value INR > 1.3 due to altered hepatic function 
16) SV value CPK > 2 x ULN 
17) Screening serum creatinine > 1.5 mg/dl 
18) Significant renal disease, including nephritic syndrome, chronic kidney disease (defined 
as patients with markers of kidney failure damage or eGFR < 60 mL/min/1,73 m2) 
calculated by MDRD 
19) Platelet count < 150 x 103/µL 
20)  AFP > 20 ng/mL with 4-phase liver CT or MRI imaging suggesting presence of liver 
cancer 
21) Known hypersensitivity to the investigational product or to any of the formulation 
excipients of the elafibranor or placebo tablet 
22) Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study is uncertain 
 
 

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5 
STUDY PROCEDURES 
The procedures performed at each visit are summarized in the study schedules (Table 1 and Table 2 
and Table 3) 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, vital signs will be measured, and the patient will be queried in the form of an open 
question regarding new or continuing events. 
During any study visit during which PROs are performed, it is recommended to be completed by the 
patient prior to the site performing any invasive procedures. 
Procedures for premature discontinuation after randomization are described in Section 5.2. 
5.1. 
SCREEN FAILURES 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure subjects. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. 
Individuals who screen failure because of a specified modifiable factor may be rescreened. 
5.2. 
PATIENT WITHDRAWAL AND PATIENT TREATMENT DISCONTINUATION RULES 
5.2.1. 
Permanent discontinuation of study drug/withdrawal from study 
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. 
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. 
The reason for permanent discontinuation of study drug should be documented in the electronic case 
report form (eCRF) and the Medical Monitor informed. If the discontinuation of study drug is due to an 
AE, the event should be documented in the eCRF. 
Some possible reasons that may lead to permanent early study drug discontinuation include: 
• 
At the discretion of the Investigator, any AE, AESI, SAE (described in Section 8.1.1 and 8.1.2), 
or significant change in a laboratory value (described in Section 6.3.1, 6.3.2, 6.3.3, 6.3.4, and 
6.3.5) or worsening or disease progression that would require in the patient’s best interest, 
initiation of any standard of care prohibited in the study. Investigators are advised to call the 
Medical Monitor prior to making such a decision 
• 
Non-permitted concomitant medication (described in Section 7.12 and 16.2) 
• 
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 
• 
Non-compliance with the study treatment 
• 
Uncooperative patient 
• 
The patient requests to stop study drug permanently. 

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Patients permanently discontinued from study drug during the DB period will perform an EOT DB visit 
within 16-30 days after the last drug intake and will continue to attend all scheduled visits until the visit 
8 (without undergoing histology or PK assessment, if applicable), or until the last completed V5 
whichever occurs first. Patients permanently discontinuing study drug during the LTE period will attend 
the EOT LTE Visit within 16 to 30 days after the last administration of study drug (as described in Section 
3.5.4). 
5.2.2. 
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. 
5.2.3. 
Replacement 
No patient replacements are permitted in this study. 
5.2.4. 
Premature Discontinuation of the Study 
Premature termination of this clinical study may occur because of a Regulatory Authority decision, 
change in opinion of the institutional review board/independent ethics committee (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 treatment at any time. 
The Sponsor reserves the right to discontinue the study 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 study materials must be collected and all case report forms (CRFs) 
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. 
In all cases IRB/IEC and Health Authorities should be informed. 
If the Investigator decides to prematurely discontinue the study, all test articles, eCRFs, and related 
study materials must be returned to the Sponsor. 

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6 
ASSESSMENTS 
6.1. 
EFFICACY AND SAFETY ASSESSMENT 
6.1.1. 
Biological assessment 
All blood samples for efficacy and/or for safety assessment will be returned and centralized by the 
central laboratory. 
A Laboratory Manual will be provided to each 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-
48 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 received. The Investigator should comment 
upon out of range parameters and assess clinical significance. 
In order to maintain the blind, ALP, GGT and 5’ NT obtained from blood samples from V2 to V8 / LVDB/or 
last V6 whichever occurs first (up to end of DB period) will be kept in blinded condition during the DB 
treatment period for each patient. Similarly, the same rule will apply to ALP, GGT and 5’-NT obtained 
from blood samples until the first visit in the LTE period (LT1), including EOT LTE and unscheduled 
visits. The Investigator will not be informed of these values until the database lock at the end of the DB 
period. 
The option to retest during the study is left to the Investigator’s judgment. During Screening, retesting 
(to be performed at Retesting and/or additional SVs) is limited to CPK, and HCV RNA (in case of positive 
HCV Ab at SV) as described Section 3.5.5 and in Table 2. 
At visits for which blood samples will be drawn, patients must be fasting for at least 12 hours. These 
visits should be scheduled in the morning. 
Both blood and urine dipstick samples will be transported to the central laboratory for testing and 
analysis except for urinary/blood myoglobin that should be tested at local laboratory when applicable. 
Local laboratory assessments are allowed for repetition of assessment of ALT, AST, TB and ALP during 
the screening period as well as for any required retest for liver function monitoring and assessment of 
urinary/blood myoglobin, when applicable. 
Local laboratory results will be entered in eCRF including corresponding normal ranges. 
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) will be measured at all visits. Both blood and urine dipstick samples 
will be transported to the central laboratory for testing and analysis. 

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6.1.1.2. 
Urinary Pregnancy Tests 
For WOCBP, serum pregnancy test will be performed at screening (and may be repeated within one 
month prior to randomization in case the screening period lasts more than 4 weeks) while urinary 
pregnancy tests will be administered at each visit from V1. Notably, the urine pregnancy test performed 
at V1 is to occur on site prior to randomization.  If such test is unclear, a follow-up serum pregnancy 
test should also be performed prior to dosing. In addition, monthly urine home pregnancy test kits will 
be provided during scheduled visits for use during non-visit months. In case of positive urinary test, a 
confirmatory serum pregnancy test must be performed at site.  
6.1.1.3. 
Serology 
Screening for hepatitis and HIV will be performed during screening and will include: 
• 
HIV Ab I/II 
• 
Anti-HAV IgM 
• 
HBsAg 
• 
HCV Ab (If positive, a HCV RNA test will be performed to determine infection status) 
6.1.1.4. 
Other Parameters 
All other parameters will be measured according to the schedule described on Table 2. 
 
6.1.2. 
Constitution of biobank  
In order to be able to test other specific parameters which could be of interest regarding the elafibranor 
development program or regarding diagnosis, prevention, or treatment of PBC or other related diseases, 
an additional amount of blood will be sampled from patients who have given their consent for these 
additional analyses by signature of the biobank ICF. 
These samples will be destroyed 3 years after final study results at the latest. 
 
6.1.3. 
Bone density by DEXA scanning 
DEXA scanning (hip and lumbar) will be performed in patients at study sites at which DEXA scan 
equipment is available and has been approved for use in this study. Study participants will have this 
exam at baseline (before randomization after the patient has been otherwise confirmed as eligible and 
up to randomization visit), at week 52 and then 2 years later as described in Table 1. 
 
6.1.4. 
Histological assessment  
For patients who consent to have liver biopsy samples collected, a liver biopsy (see Section 6.1.4.1 for 
recommendations) will be performed: 
• 
During the Screening period (unless an historical liver biopsy within 6 months before screening 
is available) 
• 
At 52 weeks of treatment 

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In addition, for any patient randomized in the study, a liver biopsy can be requested at any time in case 
of suspicion of auto-immune hepatitis or for safety monitoring at the discretion of the investigator 
(section 6.3.2 & 6.3.3).   
A Laboratory Manual will be provided to each study site. The manual will outline the collection process, 
and shipping requirements for the specific central laboratory. 
6.1.4.1. 
Recommendations related to liver biopsy 
The patient’s platelet count and PT should be checked according to local hospital standards before the 
date of liver biopsy. Local guidelines and thresholds for hemostatic parameters should be used as they 
are in everyday clinical practice. Usually a platelet count >80,000/mm3, a PT >60% or longer by no 
more than 4 seconds over the control, and a normal bleeding time are acceptable for performing 
percutaneous liver biopsy in a patient that has stopped taking any antiaggregant therapy for >5 days. 
If these conditions are not all respected, a safer option would be to perform the liver biopsy by 
transjugular route, when available. 
Sedation is recommended to be given for percutaneous liver biopsy, and should be given with caution 
in liver disease. 
The recommended biopsy procedure to be applied is: 
• 
Needle core biopsy 
• 
Biopsy obtained with a 16 or lower gauge needle 
• 
A tissue core ≥2 cm long (≥10 portal tracts) represents optimal biopsy length 
• 
Preferably obtain biopsy from the right lobe. If left lobe biopsy is used for inclusion, a left lobe 
biopsy should be used for future biopsies. 
Post-biopsy observation: It is recommended that the patient should remain in hospital at least for 6 
hours after the procedure. 
The biopsies will be sent to the central laboratory and then stained and digitalized, before being 
transfered for central reading. Biopsy slides will be blinded for patient and visit identification prior to 
central reading. 
In case the liver biopsy fragment is too small or of bad quality, thereby precluding adequate reading, 
other available slides or new slides to be prepared from an available block of tissue may be requested 
to the site. 
6.1.4.2. 
Liver biopsy reading  
Liver biopsy samples will be sent to the central laboratory where they will be stained and digitalized.  
Liver biopsy slides will be assessed and scored by at least two pathologists. Scores for fibrosis, bile duct, 
cholangitis activity, interface hepatitis activity, will be evaluated and agreed. A liver biopsy management 
plan will detail the process of management of the liver biopsy samples from collection to final 
assessment. A liver biopsy assessment protocol will detail the reading methodology to be implemented. 
 
6.1.5. 
Pharmacokinetic assessment 
Elafibranor (GFT505) and GFT1007 plasma concentrations PopPK analysis is to be done at steady-state. 
Thus the PK blood collection will be at steady state after repeated administration of elafibranor in order 
to assess its PK and the one of its main active metabolites, GFT1007, in PBC patients. GFT505 and 
GFT1007 will both be included in the PopPK analysis. 

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6.1.5.1. 
Pharmacokinetic blood sampling timepoints 
Elafibranor and its main active metabolite GFT1007 plasma concentrations will be evaluated at steady-
state after 4 weeks of treatment (V2).  
The collection of PK blood samples is to be performed at the first visit post randomization (V2) in order 
to limit as much as possible treatment compliance issues. Prior to sampling the patient, the investigator 
will have to check the patient compliance over the preceding 16 days. 
All patients (including patients under placebo in order to maintain the blind of the study) will be sampled 
with 6 sampling timepoints: predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h. 
The following restrictions should be applied to patients for the visit V2 where PK sampling are planned: 
• 
Study treatment will be taken at site under fasting conditions after the blood sampling for 
biological assessment (see section 6.1.1) and predose PK sampling and before further PK 
samplings, in this strict order. 
• 
The time of study drug intake (T0) should be at least 24h after the previous dosing. 
• 
The date and time of study drug intake the day before the visit (V2) has to be recorded as well 
as the day of the visit (V2). 
• 
The predose PK sampling has to be collected as close as possible to the study drug intake (T0) 
(within max 1h prior to T0). 
Samples should be collected as close as possible to the therotical timepoints. Exact time of sampling 
will be recorded in the eCRF.   
6.1.5.2. 
Pharmacokinetic blood handling procedures 
At each time point (predose, 0.5h, 1.5h, between 2 and 3h, 4h, and 6h), 1 tube of 6 mL blood sample 
should be drawn into lithium heparin Vacutainer® tube protected from light with foil. Plasma will be 
separated, stored and shipped as described in the laboratory manual, first to the central laboratory (as 
for all the other blood samples collected) where they will be stored until shipped to a specialized 
laboratory  for analysis. 
The exact time of sample collection will be recorded in the source documents and reported in the eCRF. 
6.1.5.3. 
Bioanalytical analysis 
The bioanalysis part will be conducted at a specialized laboratory in compliance with its Standard 
Operating Procedures (SOPs) in use. 
Elafibranor and GFT1007 will be assayed by measuring concentrations according to an analytical method 
previously developed and validated as detailed in the Bioanalytical Study Plan. 
6.1.5.4. 
Description of pharmacokinetic evaluation parameters 
PK parameters (AUCss, clearance, volumes of distribution, etc.) will be determined from elafibranor and 
GFT1007 plasma concentrations using a popPK model. A dedicated software for nonlinear mixed models 
will be used for the analysis. 
The population PK analyses will be described in a separate data analysis plan and reported in a 
standalone report.  

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An exploratory analysis will be performed to assess the relationship between PK and PD (efficacy or 
safety endpoints). If a trend is shown, an attempt to build a PKPD model using a population approach 
will be performed. Those analyses (population PK and, if applicable, population PKPD) will be described 
in a separate data analysis plan and reported in a standalone report.. 
PK parameters of elafibranor and GFT1007 will be summarized by geometric mean, SD, coefficient of 
variation, minimum and maximum, and median. 
 
6.1.6. 
Liver stiffness by transient elastography (FibroScan®) 
FibroScan® TE device (Echosens, Paris, France) is a non-invasive technique used to measure liver 
stiffness, which correlates with fibrosis. This assessment will be performed on all patients as illustrated 
by the Study General Assessment Schedule (Table 1). All sites must have designated staff trained in the 
use of the device. 
This assessment will be done the day of the visit. Failing this, it can be performed within 7 days of the 
visit. 
To ensure reliability of the assessments patients must be in a fasted state for at least 3 hours before 
the examination. Additional instructions will be provided in a separate manual. 
As presented in the paper from Corpechot et al [24], the threshold for classification of cirrhosis is ≥ 
16.9 KPa. 
6.1.7. 
Patient Reported Outcomes Questionnaires 
The following PROs will be assessed: 
a) The PBC Worst Itch NRS (Appendix 16.3.7) is a simple, self-administered PRO questionnaire 
that measures itch intensity. It uses 24-hour and 7-day recall periods and asks patients to rate 
the intensity of their Worst Itch on an 11-point scale ranging from 0 (no itch) to 10 (Worst Itch 
imaginable). Patients will record their scores once daily (24-hour recall) using the eDiary during 
the screening and Common DB periods and during study visits (7-day recall; PBC Worst Itch 
NRS-Past Week) during the Variable DB and LTE periods as outlined in Table 3. At 
randomization, the patient’s daily scores (24-hour recall) over the previous 14 days will be 
averaged to determine the baseline score for stratification and analysis; at least 4 available 
values for PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to 
randomization (for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior 
to randomization) are required for the baseline score to be calculated.    
b) The 5-D Itch scale (Appendix 16.3.3) is a questionnaire that has been validated in several 
different diseases. It assesses symptoms in terms of 5 domains: degree, duration, direction, 
disability and distribution [27]. Patients rate their symptoms over the preceding 2-week period 
on a 1 to 5 scale, with 5 being the most affected. Patients will complete the 5-D Itch scale as 
outlined in Table 3. 
c) The PBC-40 (Appendix 16.3.1) is a validated, PBC-specific, HRQoL 40 question questionnaire 
that assesses symptoms across six domains: fatigue, emotional and social, cognitive function, 
general symptoms and itch [28]. Patients respond on a verbal response scale, depending on 
the section options range from ‘never’ / ‘not at all’ / ‘strongly disagree’ to ‘always’ / ‘very much’ 
/ ‘strongly agree’. Five items (3/3 in the itch domain and 2/10 in the social domain) also include 
a ‘does not apply’ option. A score for each domain is provided (but a total score is not 
calculated), with each verbal response scale correlating to a score of 1-5 per item (0-5 on items 
with a ‘does not apply’ option) with 5 being the most affected. The PBC-40 has a 4-week recall 
period (Appendix 16.3.1). Patients will complete the PBC-40 as outlined in Table 3. 

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d) The Euro quality of life (EuroQol) EQ-5D-5L (Appendix 16.3.8) is a 6-item, standardized 
questionnaire that assesses mobility, self-care, usual activities, pain / discomfort, anxiety / 
depression, and overall health state.    
e) The ESS [29, 30] (Appendix 16.3.2) is a short, self-administered questionnaire that consists of 
eight questions asking to rate how likely it is to fall asleep in everyday situations (each question 
can be scored from 0 to 3 points; ‘0’ indicates no sleepiness, ‘3’ indicates significant sleepiness). 
It provides a total score which has been shown to relate to the patient’s level of daytime 
sleepiness (total score range 0–24 points). Patients will be asked to complete the ESS with 
regard to the level of sleepiness they experienced over approximately the past 7 days as outlined 
in Table 3. 
f) 
The PROMIS Fatigue Short Form 7a (Appendix 16.3.4) consists of seven items that measure 
both the experience of fatigue and the interference of fatigue on daily activities over the past 
week (National Institute of Health, 2007). Patients will complete the PROMIS Fatigue Short Form 
7a as outlined in Table 3. 
g) The Patient Global Impression of Change (PGIC) (Appendix 16.3.5) is a single item 5 point scale 
designed to assess the change in overall itch intensity since the baseline visit. PGIC-Itch scores 
will be captured as outlined in Table 3. 
h) The PGIS (Appendix 16.3.6) is a 1-item 5-point scale designed to assess patient’s impression of 
itch severity. The PGIS-Itch scores will be captured as outlined in Table 3. 
Of note, PGIC and PGIS are collected as anchors to facilitate the derivation of a clinically meaningful 
threshold but will not be used to measure any treatment effect. 
In order to avoid bias in the patients' responses to the questionnaires, it is recommended that site based 
assessments be completed before any other evaluations or study procedures on the day of the study 
visit and prior to discussions with the investigator or study site staff. Site procedures and assessments 
should be conducted in the following order: PROs, investigator assessments, safety and laboratory 
assessments, administration of study drug. 
 
6.2. 
OTHER SAFETY ASSESSMENTS AND ONGOING SAFETY MONITORING 
6.2.1. 
Physical Examination 
A physical examination including neurological exam will be performed at the time points specified in the 
study general assessment schedule of events (Table 1). Height will be measured at the SV only. The 
physical examination will include the following: General appearance, weight, hair and skin, lymph nodes, 
head, eyes/ears/nose, throat, neck, respiratory system, cardiovascular system, abdominal region, 
musculoskeletal system, mental status and neurological system. 
 
6.2.2. 
Vital Signs and Weight 
Blood pressure (BP), heart rate, respiratory rate and temperature will be measured [26]. Weight will be 
measured in pounds or kilograms. All measurements will be recorded in eCRF. 
 

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6.2.3. 
12 Lead ECG 
ECGs will be analyzed by the Investigator or designee. Patients are to be supine position for at least 5 
minutes prior to ECG assessments. A minimum of 3 cycles will be recorded per lead. 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 eCRF. 
 
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 
additional visit and test must be performed within 48 to 72 hours, and an assessment of 
myoglobinuria/myoglobinemia should 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 5.2.1. 
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 5.2.1. 
6.3.2. 
Liver Function Monitoring 
Patients will be closely monitored and evaluated for other causes of liver injury and for the potential of 
DILI. Relevant assessment for suspected DILI includes: 
• 
Establishing baseline values (by at least two samples obtained at least 4 weeks and no more 
than 12 weeks apart) 
• 
Obtaining a more detailed history of symptoms and prior or concurrent disease 
• 
Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
• 
Ruling out acute viral hepatitis types A, B, C, D and E; autoimmune or alcoholic hepatitis; NASH; 
hypoxic/ischemic hepatotoxicity; and biliary tract disease 
• 
Obtaining a history of exposure to environmental chemical agents 
• 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin) 
• 
Considering gastroenterology or hepatology consultations 
In addition, guidelines for management of any sign of liver function deterioration are given in the several 
subsequent sections below. 
For any of the cases below, if a patient lives in a remote area from the site, laboratory testing can be 
performed in a local lab. The results should be promptly communicated to the investigator site. 
Liver function monitoring will be done with respect to Liver Function Tests baseline values. Of note, in 
the absence of large prospective comparative data, there is little evidence to support one threshold over 
another [31] therefore the IQ-DILI best practice recommendations have been adopted for this protocol. 
The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ 

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Consortium), a science-focused, not-for-profit organization launched the IQ-DILI Initiative in 2016, 
reached consensus, and proposed the following best practices related to DILI with respect to patients 
with elevated ALT at baseline: 
- 
If ALT ≥ 3 x baseline and there is no change in TB or liver-related symptoms, repeat measures 
and initiate close observation [32] 
- 
If ALT ≥ 3 x baseline, TB is normal or elevated and liver-related symptoms (i.e., severe fatigue, 
nausea, vomiting, right upper quadrant pain), interrupt study drug and initiate close observation 
[32]  
In addition to management guidelines, the criteria used for reporting a potential DILI for adjudication 
are given below and correspond to the criteria leading to permanent study drug discontinuation. 
For any suspicion of DILI or for any other liver related event, it is left to the discretion of the investigator 
to request a liver biopsy in accordance with the local clinical standards, in order to further assess the 
case. 
6.3.2.1. 
Treatment discontinuation rule for elevated Aminotransferase (AT) values 
regardless of baseline values 
In all cases, whether baseline Aminotransferase (AT) values are normal or elevated, an increase of AT 
>10 x ULN will lead to permanent discontinuation of the patient from study drug, and scheduling of 
EOT DB/EOT LTE visit. 
6.3.2.2. 
Treatment discontinuation rules for elevated Aminotransferase (AT) values 
according to baseline values 
6.3.2.2.1. 
Monitoring of patients with normal baseline AT values 
For patients with normal baseline AT values at V1 who at any visit from V2 onwards during the treatment 
periods exhibit: 
• 
Increase in AT to ≤ 3 x ULN: no additional action required, schedule next visit as per assessment 
schedule. 
• 
Increase in AT to >3 x ULN but ≤5 x ULN: retest after 48 to 72 hours. 
If during the following retest: 
o 
AT remains >3 x ULN but ≤5 x ULN: continue the drug with close serial monitoring 
(twice a week). Frequency of repeated testing can decrease to once a week or less if 
abnormalities stabilize or the study drug has been discontinued and the patient is 
asymptomatic 
o 
AT increases to >5 x ULN: permanently discontinue patient from study drug and 
schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4). 
• 
Increase in AT >5 x ULN: retest after 48 to 72 hours. 
If during the following retest: 
o 
AT remains >5 x ULN: permanently discontinue patient from study drug and schedule 
EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4) 
o 
AT reduces to ≤5 x ULN: continue the drug with close serial monitoring (twice a week). 
Frequency of repeated testing can decrease to once a week or less if abnormalities 
stabilize or the study drug has been discontinued and the patient is asymptomatic. 
• 
Increase in AT >3 x ULN and increase in TB > 2 ULN: permanently discontinue patient from 
study drug and schedule EOT DB /EOT LTE Visit (see Section 5.2.1 and Section 3.5.4). 
• 
Increase in AT >3 x ULN and increase in INR>1.5 (in the absence of anti-coagulant therapy): 
permanently discontinue patient from study drug and schedule EOT Visit (see Section 5.2.1 and 
Section 3.5.4). 

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• 
Increase in AT >3 x ULN and fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash: permanently discontinue patient from study drug and schedule EOT 
DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4). 
• 
Increase in AT >3 x ULN and eosinophilia (> 5%) with total count > ULN: permanently 
discontinue patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and 
Section 3.5.4). 
6.3.2.2.2. 
Monitoring of patients with abnormal baseline AT values 
For patients with abnormal AT baseline values at V1 who at any visit post V1 onwards during the 
treatment periods exhibit: 
• 
Increase in AT to ≤ 3 x baseline value: no additional action required, schedule next visit as per 
assessment schedule. 
• 
Increase in AT to >3 x baseline value but ≤10 x ULN: retest after 48 to 72 hours: 
o 
If baseline value < 2 x ULN: 
 
AT increase ≤ 5 x baseline: continue the drug with close serial monitoring 
(twice a week) 
 
AT increase > 5 x baseline: permanently discontinue patient from study drug 
and schedule EOT DB/EOT LTE visit (see Section 5.2.1 and Section 3.5.4) 
o 
If baseline value > or equal 2 x ULN but < 5 x ULN: 
 
AT increase ≤ 3 x baseline: no additional action required, schedule next visit 
as per assessment schedule 
 
AT increase remains > 3 x baseline: permanently discontinue patient from 
study drug and schedule EOT DB/EOT LTE visit (see Section 5.2.1 and Section 
3.5.4) 
• 
Increase in AT >3 x baseline value and increase in TB > 2 x baseline: permanently discontinue 
patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 
3.5.4). 
• 
Increase in AT > 3 x baseline value and increase in INR by above > 0.2 compared to baseline 
INR (in the absence of anti-coagulant therapy): permanently discontinue patient from study 
drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and Section 3.5.4). 
• 
Increase in AT > 3 x baseline value and fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash: permanently discontinue patient from study drug and schedule 
EOT/EOS Visit (see Section 5.2.1 and Section 3.5.4). 
• 
Increase in AT > 3 x baseline and eosinophilia (> 5%) with total count > ULN: permanently 
discontinue patient from study drug and schedule EOT DB/EOT LTE Visit (see Section 5.2.1 and 
Section 3.5.4). 
6.3.2.2.3. 
Monitoring of patients with abnormal TB baseline values  
For patients with abnormal TB values at V1 who at any visit post V1 onwards during the treatment 
periods exhibit: 
• 
Increase in TB to > 1.5 x baseline value: retest after 48 to 72 hours 
o 
TB remains >1.5 x baseline value: continue study drug and implementation of close 
observation (testing and physical examination 2-3 times per week). Discontinuation of 
study should be considered. 
 
6.3.3. 
Auto-immune hepatitis monitoring 
For patients who at any visit post V1 onwards during the treatment periods, exhibits ALT>5 X ULN, IgG 
serum or smooth muscle autoantibody should be tested (these tests are to be done locally);  

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if IgG is >2XULN or smooth muscle autoantibody positive, a liver biopsy should be performed at an 
unscheduled visit; if moderate or severe interface hepatitis is detected on histology, AIH will be 
confirmed and patient should be discontinued from study drug (if not already discontinued according to 
discontinuation rules described in Section 6.3.2). 
 
6.3.4. 
Acute Pancreatitis Monitoring 
6.3.4.1. 
Treatment discontinuation rule for suspected acute pancreatitis 
If at any visit during the treatment period, a patient experiences serum amylase and lipase ≥ 3 x ULN, 
associated with abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back), an ultrasound exam or CT scan will be performed for the 
diagnosis of pancreatitis. If confirmed, the patient must be discontinued from the study drug 
immediately and followed up as described in Section 5.2.1. 
 
6.3.5. 
Monitoring of hepatocellular and bladder cancer 
6.3.5.1. 
Liver monitoring 
Ultrasonography of liver and analysis of AFP will be performed at baseline, & then every year (V6, V8, 
LT3, LT5 , LT7, and LT9 if applicable), AFP will be performed at LVDB, if applicable, as described in 
Table 1 and Table 2. 
6.3.5.2. 
Bladder & urinary tract monitoring 
Ultrasonography of bladder and urinary tract will be performed at baseline, & then every year (V6, V8, 
LT3, LT5 , LT7, and LT9 if applicable) as described in Table 1. 
6.3.6. 
Safety Review 
Safety oversight will be implemented under the direction of a DSMB composed of at least five 
experienced physicians (an endocrinologist, cardiologist, oncologist, hepatologist and nephrologist) and 
one independent statistician, all independent from the conduct of the study. Members of the DSMB 
should be free of conflicts of interest. The members of DSMB will review the progress of the study and 
perform a safety data review (including review of the adjudication reports issued from the CEC) on a 
regular basis (at least every six months) to ensure patient safety and preserve study integrity.  
A DSMB charter will define the membership, roles, responsibilities, rules and tasks of the DSMB. 
 
6.3.7. 
Clinical event committee 
The CEC will conduct adjudication of the clinical outcomes  and DILI events. The CEC assessment and 
adjudication will occur in a blinded (during DB period) and consistent and unbiased manner throughout 
the course of the study to determine whether the endpoint meets the protocol specified criteria. 
The CEC will be comprised of 3 hepatologists, all of them will be independent from the conduct of the 
study. 
 

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6.4. 
GUIDANCE FOR INVESTIGATORS 
6.4.1. 
Summary of safety data 
The safety and tolerability of elafibranor were confirmed in Phase 1 to Phase 3 studies. 
A Phase 1 program has been conducted to assess the safety and tolerability, as well as the PK profile, 
of elafibranor. Elafibranor daily doses ranged between 5 mg and 360 mg, with a treatment duration up 
to 18 days. Importantly a PK study in hepatic impaired subjects was recently conducted and concluded 
that no dose adjustment is required in cirrhotic patients, unless there is a safety concern. 
A Phase 2 program has been conducted to assess the safety and efficacy profile of elafibranor in patients 
suffering from cardiometabolic disorders and NASH.  
A Phase 2 study (GFT505B-216-1) in PBC was also completed and included forty five (45) patients with 
PBC and inadequate response to UCDA. This study evaluated the efficacy and safety of elafibranor at 
daily doses of 80 mg and 120 mg after 12 weeks of treatment. In the Phase 2 program, the elafibranor 
daily doses ranged between 30 mg and 120 mg, with a maximum treatment duration of 12 months. 
2157 patients with NASH and fibrosis have been randomized in a Phase 3 study (Study GFT505-315-1). 
In this study, the subjects were receiving 120 mg/day elafibranor or placebo for up to 72 weeks during 
the first treatment period, followed by a long-term treatment period to assess efficacy on progression 
to cirrhosis, all-cause mortality and liver-related clinical outcomes as measured by the onset of any of 
the listed adjudicated events of portal hypertension/cirrhosis related events. Given the failure to meet 
the predefined primary surrogate efficacy endpoint (i.e. NASH resolution without worsening of fibrosis) 
and following further in-depth review of the efficacy dataset, despite absence of safety issue, it was 
decided to prematurely terminate the study in October 2020 following sponsor decision. 
Based on the cumulative experience gathered to date, gastro-intestinal disorders (abdominal pain, 
nausea , vomiting, diarrhoea, constipation) are considered common non-serious adverse reactions 
reasonably associated with elafibranor; most of them are of mild to moderate severity. In addition, 
these AEs are to be monitored as AESIs (see Section 8.1.2) as well as other AESIs which could be 
considered as class effect AEs.  
Additional details are provided in IB. 
Regarding specific monitoring, although no signal for increase in CPK has been observed in the clinical 
studies, given the known effects of PPAR agonists on the increase of CPK enzyme, this parameter is 
monitored in clinical studies. For this reason, it is recommended that investigators review these lab 
results in the course of clinical studies. 
Other known effects of PPAR agonists include the increase of creatinine, which was observed in our 
clinical studies, in a range of 1-10%. This increase was reversible at EOT. This should also be monitored 
in clinical studies. 
Liver enzymes will also be monitored in clinical studies, with specific attention paid to DILI. In the 
elafibranor clinical development program to date, there has been no imbalance in DILI events in 
individuals who received elafibranor compared to individuals who received placebo. 
Based on the findings of nonclinical reproductive and developmental toxicity studies performed to date, 
and in the absence of human pregnancy data, elafibranor may be classed in the “Possible human 
teratogenicity/fetotoxicity in early pregnancy” risk category according to the Clinical Trial Facilitation 
Group (CTFG) document Recommendations related to contraception and pregnancy testing in clinical 
studies [33]. 

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As such, all clinical studies with elafibranor including WOCBP request a negative pregnancy test before 
Randomization, effective contraceptive measures throughout the study and mandatory study 
discontinuation upon becoming pregnant.  Contraception should be maintained up to 1 month after the 
last drug intake. Pregnancy tests should be repeated as stated in the Table 2.  
For further details, refer to the IB. 
 
6.4.2. 
Benefit/risk assessment 
Clinical studies completed to date have not raised any major safety concerns associated with elafibranor 
treatment, thus providing a favorable efficacy/safety profile for the drug candidate. 
A Phase 2 study in PBC subjects who had an inadequate response to UDCA demonstrated improvement 
in GGT, lipid and inflammatory markers. Moreover, a significant decrease of ALP levels was observed, 
resulting in significant treatment effects versus placebo on the primary endpoint, whilst also meeting 
the composite endpoint used for drug registration (i.e. serum ALP <1 .67 x ULN, an ALP decrease > 
15%, and TB < ULN). 
Plasma concentrations and PK parameters measured for GFT505 and GFT1007 in subjects with PBC 
were similar with that measured in healthy volunteers in previous studies with comparable dose 
regimen. The results obtained in this study suggest that the PK of GFT505 and its active metabolite 
(GFT1007) are not modified in subjects with PBC. 
Despite this favorable benefit-risk profile, an independent DSMB will be established in order to review 
the safety of the treatment during the study in an unblinded manner, to protect patient welfare and 
preserve study integrity (Section 6.3.6). 
In conclusion, the safety data collected so far and the current knowledge on GFT505 confirm the 
favorable balance between risks and anticipated efficacy/benefits. 
 

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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 white to off-white round coated tablets 
with no printed inscription. The tablet contains elafibranor and inactive ingredients (microcrystalline 
cellulose, povidone, croscarmellose, anhydrous colloidal silica, magnesium stearate, Opadry II HP 
85F18422). 
Placebo tablets to match elafibranor 80 mg will be provided as a white to off-white round coated tablet 
with no printed inscription. Of note, in the placebo tablet formulation, lactose monohydrate is used for 
replacing the active substance. 
Additional information can be found in the IB. 
 
7.2. 
PACKAGING AND LABELING 
7.2.1. 
Packaging 
Elafibranor/placebo: 
The primary packaging is composed of opaque polyamide/aluminum/PVC complex and aluminum foil 
blisters. This has been shown to be a suitable primary packaging for tablets. 
Blisters, containing 7 tablets each, will be packed in child proof wallets. 
Each childproof wallet will contain 5 blisters (covering approximately one month of treatment). Three 
wallets (covering the period between each visit) will be packaged inside a period box. 
7.2.2. 
Labeling 
All labels for study drugs will meet all applicable requirements of the US 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 study 
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.”  
 
7.3. 
DOSAGE AND ADMINISTRATION OF ELAFIBRANOR AND PLACEBO 
Patients will be informed to take 1 tablet per day of elafibranor 80 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 DB treatment period, the Investigator will register the patient 
in the IXRS system to randomize him/her. 
The Investigator will log into the system using his identification number and access code. The IXRS will 
then allocate the patient to a treatment group (placebo or elafibranor 80 mg) through a treatment 
number. 
A specific IXRS manual will be provided to the pharmacy and investigator site. 
The randomization list will be generated by the Clinical Research Organization (CRO) for data 
management & statistics, and will be kept under blinded condition to the study patients, investigator 
site, sponsor and sponsor representative until the database lock and the Sponsor authorization to 
unblind the study. 
 
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 confirm each study drug dispensation in the IXRS. 
At every visit from V1 up to visit V6 (apart from visit V2), every randomized patient will be delivered 
with one period box. 
From visit V6, two period boxes will be delivered at each site visit. 
 
7.7. 
TREATMENT REPLACEMENT 
Treatment replacement, if needed, will be explained in a specific IXRS procedure manual. 
 
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 SV. The number will also be reported in the 
eCRF. Upon completion of the SV, eligible patients will be randomly assigned to elafibranor 80 mg or 
placebo at the randomization visit. 
 

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7.9. 
PROCEDURE FOR UNBLINDING 
The randomization code may be broken by the Investigator when urgent action is required for the 
clinical management of the patient. For each patient, the list of treatment numbers allocated to the 
patient will be stored in the IXRS. The Investigator will be able to unblind any treatment period box that 
was dispensed to the patient by connecting to the IXRS (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 IXRS will verify the 
authorization to unblind the entered treatment period box number and the screen will then display the 
treatment group. When completed, a blinded confirmatory email will be sent to the Investigator and the 
Sponsor. The reason for unblinding should be clearly and fully documented by the Investigator. 
Unblinding of treatment arm will occur after the database lock of the DB period and the Sponsor 
authorization. 
 
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 period box/wallets. Compliance will be checked by 
the Investigator during those visits and recorded in the eCRF. 
The compliance will be collected within the 16 days prior the Visit V2 for further PK assessment. 
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, pharmacist or designee will acknowledge receipt for each study treatment on the day 
of receipt. A study drug accountability record should be maintained by the person responsible for 
dispensing the study drug to the patient. 
All partially used or unused treatments will be inventoried by the monitor during and at the conclusion 
of the study. 
Upon 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 SOP for study drug destruction, the site may destroy used and unused 
study drugs in accordance with the site SOP and always after the drug accountability has been 
performed by the monitor. 
If study drug is destroyed at the site, the Investigator must maintain accurate records for treatment 
cartons destroyed recording: 
• 
Treatment carton (kit) number 
• 
Quantity destroyed 
• 
Method of destruction 
• 
Person who disposed of the study drug 
 

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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 Non-
permitted medication and condition, Appendix 16.2). 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 
Some medications are not allowed within the timeframe given in Appendix 16.2. 
If it is identified after Randomization that these non-permitted drugs have been administered to a 
patient within the excluded timeframes, the decision to permanently discontinue the patient will be 
discussed with the medical monitor (see Section 5.2). 
 
7.12.3. 
Permitted Medication Under Conditions 
The following medications are permitted under the condition of steady dosage prior to screening: 
• 
UDCA if taken for at least 12 months (and stable dose for ≥ 3 months) prior to screening (SV1) 
• 
Statins and ezetimibe provided the dosage is kept stable for at least 2 months prior to screening 
• 
Colchicine provided the dosage is kept stable for at least 3 months prior to screening. 
• 
Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or 
sertraline) must be on a stable dose for ≥ 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 bias. 
In the event that additional concomitant therapy becomes necessary during the study, 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 (AEs) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical (investigational) product and which does not necessarily have a causal relationship with 
this treatment will be considered as an AE. The term AE is synonymous with the term “adverse 
experience” as used by the FDA. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding 
or, 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 and 
breastfeeding. 
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 study 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 SV 
that do not worsen 
• 
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. 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event 
is a treatment-emergent AE. An AE is considered to be treatment emergent if (1) it is not present when 
the active phase of the study begins and is not a chronic condition that is part of the patient’s medical 
history, or (2) it is present at the start of the active phase of the study or as part of the patient’s medical 
history, but the severity or frequency increases during the active phase. The active phase of the study 
begins at the time of the first dose of the study drug. The active phase of the study ends at the last 
study visit. 

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8.1.2. 
Adverse events of special interest (AESIs) 
AESIs are treatment emergent AEs corresponding to the conceptual definition of:  
• 
CPK elevations of severe intensity or leading to permanent study drug discontinuation 
• 
Muscle injury symptoms of severe intensity corresponding to:  
o 
Muscle pain or Myalgia 
o 
Muscle spasms or Tremor 
o 
Muscle weakness 
• 
Transaminases elevations from baseline of severe intensity or leading to permanent study drug 
discontinuation 
• 
Autoimmune hepatitis 
• 
Liver injury events of severe intensity corresponding to:  
o 
Hepatic injury 
o 
Hepatic impairment 
o 
Hepatic failure  
• 
Gastrointestinal symptoms of severe intensity corresponding to: 
o 
Abdominal pain 
o 
Constipation 
o 
Diarrhea 
o 
Nausea 
o 
Decreased appetite 
o 
Vomiting 
o 
Acute cholecystis 
o 
Acute pancreatitis 
• 
Fatigue and Asthenia of severe intensity 
• 
Serum creatinine elevations of severe intensity or leading to permanent study drug 
discontinuation 
• 
Renal injury events of moderate or severe intensity corresponding to: 
o 
Renal injury 
o 
Renal failure 
o 
Renal impairment 
o 
Renal colic 
• 
Neurological abnormalities of moderate to severe intensity corresponding to: 
o 
Tremor 
o 
Ataxia 
o 
Fasciculations 
• 
Parkinson’s Disease 
• 
Peripheral edema of moderate to severe intensity 
• 
Weight gain of more than 5% from baseline 
• 
Major Adverse Cardiovascular Events corresponding to: 
o 
Non-fatal myocardial infarction/unstable angina 
o 
Non-fatal stroke 
o 
Unstable Angina  
o 
Hospitalization for Heart Failure  
o 
Coronary Revascularization (bypass or percutaneous coronary intervention ) 
Treatment emergent Pregnancy and outcomes of Pregnancy will be considered as AESIs, and are 
described in the Section 8.6.1. 
 
8.1.3. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 

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• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
or 
• 
Is a congenital anomaly/birth defect. 
8.1.4. 
Clarification on Serious Adverse Events 
• 
Death is an outcome of an AE, not an AE in itself. 
• 
A SAE may occur even if the patient was not being treated with the study drug at the 
occurrence of the event. 
• 
Life-threatening means that patient is at immediate risk of death.  
• 
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. Of note, 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. 
• 
Only a persistent or significant or incapacitating disability is implied. This item refers to a 
substantial disruption of a person’s ability to conduct normal life functions. Thus, disability is 
not intended to include experiences of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma. 
• 
Congenital anomaly/birth defect includes foetal malformations associated with spontaneous 
abortions or elective abortions. 
• 
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 also usually be considered serious. 
• 
Any illnesses reported before starting active treatment or AE meeting the criteria of seriousness 
(as defined above) and considered to be possibly related (according to the Investigator) to any 
study-specific procedure (e.g. wash-out period, laboratory testing procedure, etc…) must be 
reported as SAE. 
8.1.5. 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is noxious and 
unintended at any dose and that is considered causally related to an investigational medicinal product. 
A serious ADR (SADR) is an ADR which meets the seriousness criteria. 
 
8.1.6. 
Unexpected Adverse Event 
Expectedness is assessed by the Sponsor. An unexpected AE is defined as an event that has a nature 
of severity or specificity that is not consistent with the applicable IB 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 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 AE have occurred at each visit from the date of 
consent. The patient will be questioned in a general manner to determine specific symptoms without 
offering the patient any suggestion. 
8.2.1. 
Intensity Assessment 
The intensity of the AE will be graded as follows: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type 
causing no loss of time from normal activities. Symptoms do not require therapy or a medical 
evaluation; signs and symptoms are transient. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the subject 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 subject’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 CRF. 
The Investigator will record the relation to the study treatment according to the following causality 
terms: 
• 
Related: the AE or laboratory test abnormality 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 or other drugs. 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 study drug taken, 
preplanned elective medical intervention, or incompatible temporal relationship. 
• 
Not assessable: the report suggesting an adverse reaction cannot be judged because 
information is insufficient or contradictory and data cannot be supplemented or verified. 
8.2.3. 
Action Taken and Outcome 
The Investigator will record the action taken with drug and outcome of the event for each AE according 
to the following: 
Action taken with study drug 
• 
Drug withdrawn – in case a patient is permanently withdrawn from the study drug 
• 
Drug interrupted – in case the study drug is temporarily withdrawn 

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• 
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 AE 
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 last study visit of the patient. Whenever possible, 
symptoms should be grouped as a single syndrome or diagnosis. The Investigator should specify the 
date of onset, maximal intensity, action taken with respect to study drug, corrective therapy given, 
outcome, and his/her opinion as to whether there is a reasonable possibility that the AE was caused by 
the study drug. 
AE reporting begins from signature of the patient ICF at the first SV and ends at the last study visit. 
 
8.3.2. 
Reporting a SAE or an AESI 
SAE reporting begins from signature of the patient ICF and ends at the last study visit. 
AESI reporting starts from first study drug intake and ends at study end for each patient. 
Investigators must notify by email, or fax the Sponsor of all SAEs or AESIs IMMEDIATELY (within 
24 hours of the Investigator becoming aware of the event) regardless of the causality. The 
Investigator will be requested to supply as much detailed information regarding the event that is 
available at the time of the initial contact (such as examinations carried out and laboratory results). 
The Investigator is also required to submit follow-up reports to Sponsor or its representative 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. Copies of additional laboratory tests, consultation reports, post mortem reports, 
hospital case reports, autopsy reports, and other documents should be sent when requested and 
applicable. 
In case of death, a comprehensive narrative report of the case should be prepared by the Investigator 
and sent to the Sponsor with the SAE/AESI form, retaining a copy on site with the CRF. If an autopsy 
is performed, copy of autopsy report should be actively sought by the Investigator and sent to the 
Sponsor as soon as available, retaining a copy on site with the CRF. 

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Initial and follow-up report will be completed by the Investigator using appropriate template provided 
to him by the Sponsor. 
The expected / unexpected status of the serious and related AE will be judged by the Sponsor or its 
designated Representative with regards to the reference documents (IB). 
The Sponsor or its designated Representative will report all the relevant safety information to the 
concerned IRB/IEC concerned according to the country specific requirements. 
The Investigator must also fulfill his/her obligation regarding AE reporting according to the law in force 
in his/her country. 
 
8.3.3. 
Follow-up 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably 
he/she should follow-up the outcome of any AE until the return to normal or until consolidation of the 
patient condition. 
The patient must be followed-up until clinical recovery is complete and laboratory results have returned 
to normal, or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that additional investigations may be requested by the Sponsor, notably 
for the potential related AEs, 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 
AES OR SAES 
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. 
Reporting timelines for AEs and SAEs/AESIs are described respectively in Section 8.3.1 and Section 
8.3.2 
 

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8.6. 
SPECIAL SITUATION REPORTS 
8.6.1. 
Pregnancy 
In case of pregnancy a communication will be sent by the Investigator to the Sponsor by emailing a 
completed pregnancy form within 24 hours of his/her knowledge of the pregnancy. 
Pregnancies of females partners of male patients exposed to study drug should also be reported to the 
Sponsor using the corresponding pregnancy form, provided that females partners sign the 
corresponding and separate ICF. 
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 study drug exposure to an 
embryo or fetus and to follow up on the outcome of the pregnancy. 
The Investigator will contact the patient at the expected time of delivery for follow-up. If the outcome 
of pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or therapeutic 
abortion, stillbirth, neonatal death, congenital anomaly, birth defect), the Investigator should follow the 
procedure for reporting SAEs/AESIs as detailed in Section 8.3.2. 
 
8.6.2. 
Medication Error 
Medication error is defined as an unintentional error in the prescribing, dispensing, or administration of 
a medicinal product while in the control of the healthcare professional, patient, or consumer. All 
medication errors will be documented in the eCRF and, in case of any potential risk to patient safety, 
would be reported as appropriate. 
 
8.6.3. 
Misuse 
This refers to situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the protocol. All misuse will be documented in the eCRF and, in case of any potential 
risk to patient safety, would be reported as appropriate. 
Additional information can be found in the IB. 
 
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. Clinical judgment should always be 
applied. 
Additional information can be found in the IB. 
 

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8.6.5. 
Abuse 
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which 
is accompanied by harmful physical or psychological effects. 
Additional information can be found in the IB. 

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9 
STATISTICAL METHODS AND DATA ANALYSIS 
This section is an overview of the key elements of the statistical analysis for this study. Further details 
on statistical reporting and analyses will be contained in a separate statistical analysis plan (SAP). This 
SAP may be revised during the study only to accommodate protocol amendments and to make changes 
to adapt to unexpected issues in study execution and data collection that could affect planned analyses. 
In all circumstances, a final SAP should be issued prior to database lock and treatment unblinding. The 
first approved version of the SAP should be available within 3 months of first patient randomized and 
before the first DSMB data review meeting. 
Descriptive summary statistics for continuous variables will include the number of patients, mean, 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. 
 
9.1. 
ESTIMANDS CONSIDERATIONS 
The primary objective of the study is to evaluate the effect of elafibranor (80 mg/day) on cholestasis 
over 52 weeks of treatment compared to placebo. 
The cholestasis is predominantly characterized by elevation of serum ALP. In the Phase 2 study, a 
significant effect of elafibranor on ALP serum levels was observed from the first visit following baseline 
and was reinforced up to the end of the active treatment period. Thus, a rapid decrease of the ALP 
serum levels in elafibranor group and no change in placebo group can be expected. 
To limit the occurrence of intercurrent events (ICEs) such as study treatment discontinuations due to 
lack of efficacy and/or use of rescue medication such as OCA, the patients and the investigators will 
remain blinded of the ALP, GGT and 5’ NT results until the dabase lock and the Sponsor authorization 
to unblind the study. Thus, no between group imbalance in the occurrence of these events that might 
bias the treatment effect estimate in favor of elafibranor is expected. 
As detailed below, in line with ICH E9 (R1) addendum; five attributes (treatment condition ,population, 
endpoint, ICEs and population level summary) have been specified to translate the primary objective 
into treatment effect that is to be estimated (estimands): 
• Primary estimand 
The composite strategy imputing non response for patients who experienced ICEs prior to week 52 will 
be applied. 
- 
A. Treatment condition: Administration of Elafibranor or Placebo on top of UDCA or in subjects 
intolerant to UDCA, 
- 
B. Population: Randomized patients with PBC and Inadequate Response or Intolerance to UCDA 
- 
C. Endpoint: Response to treatment (binary variable) indicating a successful response at week 
52 for a subject with ALP <1.67 x ULN, TB ≤ ULN and ALP decrease ≥ 15%, and who does not 
stop prematurely the study treatment nor use any rescue therapy, 
- 
D. Intercurrent events: To be considered as non response irrespective of data after the study 
treatment discontinuation or use of rescue therapy being missing or not, 
- 
E. Population-level summary: Between treatment group difference in response proportions. 
The primary estimand can be defined as the between treatment group difference in proportions of 
patients, from all randomized patients, achieving response at week 52, defined as ALP < 1.67 x ULN, 

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TB ≤ ULN and ALP decrease ≥ 15%, and not stopping prematurely the study treatment nor using rescue 
therapy. 
In addition, two strategies will be explored as supplementary analysis: 
- 
The hypothetical strategy will be investigated comparing the potential outcomes that 
would have been observed at week 52 between the treatment arms as if: 
o 
The patients who experienced an ICE would follow their initial randomized 
treatment 
o 
The patients who experienced an ICE from both arms would continue on 
placebo 
In addition, a tipping point analysis will explore various scenarios among the hypothetical strategy where 
missing outcomes experienced after an ICE vary independently from Elafibranor and placebo groups 
- 
The treatment policy strategy will be investigated where patients are classified as 
responders based on their outcome value at week 52 regardless of treatment 
discontinuation or use of rescue therapy. 
 
• Key secondary estimands 
Key-secondary endpoint: Response to treatment based on ALP normalization at week 52. 
The composite strategy imputing non response for patients who experienced ICEs prior to week 52 will 
be applied. 
- A. Treatment condition: Administration of Elafibranor or Placebo on top of UDCA or in subjects 
intolerant to UDCA, 
- B. Population: Randomized patients with PBC and Inadequate Response or Intolerance to UCDA, 
- C. Endpoint: Response to treatment (binary variable) indicating a successful normalization of 
ALP at week 52 without stopping prematurely the study treatment not using any rescue therapy, 
- D. Intercurrent events: To be considered as non response irrespective of data after the study 
treatment discontinuation or use of rescue therapy being missing or not, 
- E. Population-level summary: Between treatment group difference in response proportions. 
The key secondary estimand can be defined as the between treatment groups difference in proportions 
of patients, from all randomized patients, who successfully normalized their ALP at week 52 and who 
do not prematurely stop the study treatment nor use any rescue therapy. 
The same hypothetical and treatment policy strategies as for the primary estimand will be applied as 
supplementary and sensitivity analyses. 
Key-secondary endpoint: Change in pruritus from baseline through week 52 based on PBC Worst Itch 
NRS in patients with baseline PBC Worst Itch NRS score ≥4. 
The hypothetical strategy assuming that patients who experienced an ICE would have continued within 
their treatment arm will be applied. 
- A. Treatment condition: Administration of Elafibranor or Placebo on top of UDCA or in subjects 
intolerant to UDCA, 
- B. Population: Randomized patients with PBC and Inadequate Response or Intolerance to UCDA, 
- C. Endpoint: Change from baseline through week 52 in PBC Worst Itch NRS   in patients with 
baseline PBC Worst Itch NRS score ≥4, 
- D. Intercurrent events: Any outcome value collected after a treatment discontinuation or use of 
rescue therapy will be considered as missing, 
- E. Population-level summary: Between treatment group difference in mean changes from 
baseline. 

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The key secondary estimand can be defined as the between treatment groups difference in PBC Worst 
Itch NRS mean change from baseline from randomized patients with baseline PBC Worst Itch NRS score 
≥4 through week 52 or week 24 assuming they continued the assigned treatment after they experienced 
an ICE.  
As for the key binary endpoints, a tipping point analysis point analysis will be performed to explore 
several scenarios where missing outcomes experienced after an ICE vary independently from Elafibranor 
and placebo groups.  
In addition, the treatment policy strategy will be investigated where all outcome values until week 52 
will be used regardless of treatment discontinuation or use of rescue therapy. 
Key-secondary endpoint: Change in pruritus from baseline through week 24 based on PBC Worst Itch 
NRS in patients with baseline PBC Worst Itch NRS score ≥4. 
The estimand approach for the change in pruritus from baseline through week 24 based on PBC Worst 
Itch NRS in patients with baseline PBC Worst Itch NRS score ≥4 will be the same as defined for week 
52. 
 
9.2. 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
Random allocation will be made to the 2 treatment groups (elafibranor and placebo) in a 2:1 ratio basis 
and stratified by the following factors: 
1) ALP > 3 x ULN or TB > ULN: Yes/No 
2) PBC Worst Itch NRS score (averaged over the 14 days preceding randomization) ≥ 4: Yes/No 
During the LTE period, all patients will receive elafibranor 80 mg. 
 
9.3. 
ENDPOINTS 
9.3.1. 
Primary Endpoint 
Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB ≤ ULN and ALP decrease ≥ 
15%. 
 
9.3.2. 
Secondary Endpoints 
Key Secondary Endpoints 
1-Response to treatment based on ALP normalization at week 52. 
2-Change in pruritus from baseline through week 52 on PBC Worst Itch NRS in patients with baseline 
PBC Worst Itch NRS score ≥4. 
3-Change in pruritus from baseline through week 24 based on PBC Worst Itch NRS in patients with 
baseline PBC Worst Itch NRS score ≥4   
Other Secondary Endpoints 
1) Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks 
2) ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52 

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3) Response to treatment at week 52 according to: 
a) ALP < 1.5 x ULN, ALP decrease ≥ 40% and TB ≤ ULN 
b) ALP < 3 x ULN, AST <2 x ULN and TB < 1 mg/dL (Paris I) 
c) ALP ≤ 1.5 x ULN, AST ≤ 1.5 x ULN and TB ≤ ULN (Paris II) 
d) TB response rate of 15% change 
e) Normalization of abnormal TB and/or albumin (Rotterdam) 
f) 
TB ≤ 0.6 x ULN 
g) ALP ≤ 1.67 x ULN and TB ≤ 1 mg/dL [1] 
h) No worsening of TB defined as level of TB at week 52 < ULN or no increase from baseline 
of more than 0.1XULN at week 52 
i) 
Complete biochemical response defined as normal ALP, TB, AST, ALT, albumin and INR 
4) PBC risk scores at week 52: UK PBC score and GLOBE score 
5) Response based on the normalization of bilirubin at week 52 
6) Response based on the normalization of albumin at week 52 
7) Change from baseline to week 52 in hepatobiliary injury and liver function as measured by 
AST, ALT, GGT, 5’ NT, total and conjugated bilirubin, albumin, INR and ALP fractionated 
(hepatic) 
8) Change from baseline to week 52 in biomarkers of inflammation as measured by hsCRP, 
fibrinogen, haptoglobin and TNF- 
9) Change from baseline to week 52 in immune response as measured by IgG and IgM 
10) Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis 
as measured by ELF (HA, PIINP, TIMP-1), PAI-1, TGF-β, CK-18 (M65 and M30), Pro-C3 and 
liver stiffness measured by TE (continuous) 
11) Change from baseline to week 52 in lipid parameters as measured by TC, LDL-C, HDL-C, 
calculated VLDL-C and TG 
12) Change from baseline to week 52 in FPG 
13) Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as 
measured by bile acids, C4 and FGF-19 
14) Proportion of responders in PBC Worst Itch NRS according to clinically meaningful change; at 
least 30% reduction; and one point, two points or three points decrease in score from baseline 
through week 52 and through week 24 in patients with a baseline NRS score ≥ 4 
15) Proportion of patients with no worsening of pruritus from baseline through week 52 and 
through week 24 measured by the PBC Worst Itch NRS 
16) Change from baseline to week 52 in 5D-Itch 
17) Change from baseline to week 52 in PROMIS Fatigue Short Form 7a 
18) Change from baseline to week 52 in ESS 
19) Change from baseline to week 52 in PBC-40 
20) Change from baseline to week 52 in health utility as measured by EQ-5D-5L 
21) Change from baseline to week 52 in serum markers of bone turnover and in bone mineral 
density (hip and lumbar) assessed by DEXA scanning  
22) Onset of clinical outcomes described as a composite endpoint composed of: 
a) MELD-Na > 14 for patients with baseline MED-Na <12 

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b) Liver transplant 
c) Uncontrolled ascites requiring treatment 
d) Hospitalization for new onset or recurrence of any of the following: 
i) 
variceal bleed 
ii) 
hepatic encephalopathy defined as West-Haven/Conn of 2 or more 
iii) spontaneous bacterial peritonitis 
e) Death 
23) Safety and tolerability as assessed by: 
a) SAE, AE, AESI, physical examination, vital signs, medical history, ECG 
b) Chemistry and hematology 
c) Liver markers 
d) Renal biomarkers (including urinalysis) 
e) Other biochemical safety markers 
24) PK assessed by GFT505 and GFT2007 concentrations measurement in plasma 
Additionally, the same endpoints as for the DB period (except histology – if applicable - and PK 
assessment) will be collected over the LTE period to assess the maintenance of efficacy and safety of 
the treatment.  
9.3.3. 
Exploratory Endpoints (related to histological assessments) 
1) Change from baseline in the histological scores: 
a) Fibrosis stage according to Nakanuma scoring  
b) Bile duct loss score 
c) Cholangitis activity 
d) Interface Hepatitis activity 
e) Stage of disease (Sum of Fibrosis stage by Nakanuma and Bile duct loss score) 
f) Other exploratory scores (Fibrosis according to Ishak scoring, portal inflammation, ductular 
reaction, cholestasis and concentric periductal fibrosis) 
2) Correlation between histological fibrosis scores (Nakanuma and Ishak scores) and non invasive 
markers of fibrosis (liver stiffness, ELF test and ProC3) 
9.4. 
ANALYSIS SETS 
The following analysis sets will be used in this study: 
• 
Screened set: all patients who signed ICF. This set will be used to summarize disposition. 
• 
ITT set: all randomized subjects. This set will be used to summarize efficacy. 
• 
PP set: all subjects from the ITT set without any major protocol deviation affecting the primary 
efficacy endpoint. 
• 
SS: all subjects who were administered at least one dose of study drug. This set will be used to 
summarize safety. 
• 
PKS: All patients who were administered at least one dose of study drug and have at least 
one post-dose PK sample. Moreover, patients of the PK set must have data for time of dosing, 
time of sampling and amount of study drug administered. Whereas all patients are sampled 

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in order to maintain the blind, the pharmacokinetics set applies only to patients under 
elafibranor. 
• 
Exploratory (Histological) set: All subjects from the ITT set who consent to have liver biopsy 
samples collected at baseline and/or week 52 
Patients in the ITT and PP sets will be analyzed based on randomized treatment. Patients in the SS will 
be analyzed based on actual treatment received. 
 
9.5. 
ANALYSIS OF PRIMARY ENDPOINT 
The null hypothesis for response to treatment based on the primary endpoint is that there is no 
difference in response rates between elafibranor and placebo groups. The alternative hypothesis is that 
there is a difference in response rates between both groups. The null hypothesis will be tested at a two-
sided alpha of 0.05 (see Section 9.6). The efficacy analysis will be performed at the end of the common 
DB period (week 52) only, but descriptive statistics will be provided over the entire DB period (up to 
week 104). 
The number and percentage of patients with favorable response to treatment will be summarized by 
treatment group at the end of the 52 weeks of the common DB treatment period as well as at the end 
of the overall DB period (either V6/V8/LVDB). The response rates (ALP < 1.67 x ULN and TB ≤ ULN and 
ALP decrease ≥ 15%) at week 52 will be compared between the treatment groups using the exact 
Cochran-Mantel-Haentzel test stratified by the randomization strata. The estimate of the odds ratio, its 
95% CI and the corresponding p-value will be provided. The main analysis will be based on the ITT. To 
assess the robustness of the results, the same analysis will be replicated on the PP set. 
A sensitivity analysis to the statistical model will be performed on both ITT and PP sets, using an exact 
logistic regression model with treatment group and randomization strata as factors. 
Subjects who stopped prematurely the study treatment will be considered as non-responders. 
Three supplementary/sensitivity analyses imputing outcome experienced after an ICE at Week 52 will 
be applied using relevant multiple imputation methods. The imputations will be based on patients 
completing the week 52 treatment period and relevant baseline covariates: 
1) Outcomes will be imputed assuming that patients would follow their initial treatment (rather 
than switching to placebo after discontinuation). Therefore, the treatment arm will be included 
in the imputation model as a covariate or separate models will be fitted by treatment arm. 
2) Outcomes will be imputed for both placebo and treatment dropouts as if they would continue 
on placebo (using placebo-based multiple imputation (PBI)). 
3) A tipping point analysis will be performed where outcomes will be imputed assuming that the 
missing outcomes on the two arms vary independently.  
A last supplementary analysis will use outcome value at week 52 regardless of treatment discontinuation 
or use of rescue therapy. 
Further details will be provided in the SAP. 
 
 

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9.6. 
OTHER STATISTICAL ANALYSIS 
9.6.1. 
Key secondary endpoints 
The number and percentage of patients with favorable response to treatment (according to ALP 
normalization) will be described at the end of the common DB treatment period and at the end of the 
overall DB period (either V6/V8/LVDB), and the same statistical methods as for the primary endpoint 
will be applied to evaluate the treatment effect at week 52. 
The change from baseline in PBC Worst Itch NRS score through week 52 or through Week 24, in patients 
with baseline PBC Worst Itch NRS score ≥4, will be summarized by treatment group using monthly 
scores computed every 28 days and will be compared using a MMRM with stratification factors as fixed 
factors. The statistical model will be used to calculate the mean treatment difference (elafibranor - 
placebo), 95% CI and the corresponding p-value. The main analysis assumes that patients who 
experienced an ICE would have continued within their treatment arm. A tipping point sensitivity analysis 
will evaluate the impact on imputing outcomes in both treatment arms independently. A supplementary 
analysis based on treatment policy will use outcome values at week 52 regardless of treatment 
discontinuation or use of rescue therapy. Additionally, the PBC Worst Itch NRS-Past week score obtained 
during the variable DB period will be described. 
The same analyses as described above for the change from baseline in PBC Worst NRS score through 
week 52 will be repeated for the change from baseline in PBC Worst NRS score through week 24. 
All key secondary endpoints will be analysed on ITT and PP sets. 
 
9.6.2. 
Other secondary endpoints 
During the DB period 
The continuous endpoints will be described all along the DB period. At week 52, they will be compared 
between treatment groups using the MMRM with stratification factors as fixed factors. The statistical 
model will be used to estimate the mean treatment difference and its 95% CI. As for the key secondary 
endpoint, patients who will experience an ICE will be analyzed as if they would have continued within 
their treatment arm. 
The categorical endpoints will be described at week 52 and at the end of the DB period, and will be 
analyzed using the exact Cochran-Mantel-Haentzel test stratified by the randomization strata. The 
statistical model will be used to estimate the odds ratios and its 95% CI. As for the primary endpoint, 
subjects with missing data will be considered as non-responders. 
All the analyses of other secondary endpoints will be performed based on the ITT and additionally, on 
the PP. 
Further details will be provided in the SAP. 
PK assessment are described in Section 6.1.4. The statistical considerations applicable to the popPK 
modeling will be fully described in a dedicated Analysis Plan (popPK SAP). 
 
During the LTE period 
All the endpoints defined as primary or secondary endpoints (apart from histology – if applicable - and 
PK endpoints) will be assessed during the LTE period at the appropriate timepoint to assess the 

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maintenance of efficacy of the treatment. The endpoints will be summarized by treatment group using 
descriptive statistics based on both ITT and PP. 
 
9.6.3. 
Subgroup analyses 
Exploratory analyses of the primary and key secondary endpoints will be done for the following 
subgroups: 
• 
Age (< or  ≥ 65 years) 
• 
Gender 
• 
Race 
• 
UDCA treatment at baseline (Yes/No) 
• 
Prior OCA treatment (Yes/No) 
• 
ALP level at baseline (≤ or > 3 x ULN) 
• 
TB at baseline (≤ or > 1 x ULN) 
• 
TB at baseline > ULN or albumin at baseline < LLN (Yes/No) 
• 
TB > 0.6 x ULN (Yes/No) 
• 
Geographic region 
• 
PBC Worst Itch NRS score ≥ 4 (Yes/No) 
• 
ALP > 3 x ULN or TB > ULN (Yes/No) 
• 
Cirrhotic defined by Liver stiffness at baseline ≥ 16.9KPa at Fibroscan exam (Yes/No) and/or 
cirrhosis on histology 
• 
Advanced disease stage defined as liver stiffness at baseline >10 kPa at Fibroscan exam and/or 
bridging fibrosis or cirrhosis on histology 
 
Forest plots will be generated for each endpoint for patients in the ITT population. Further details will 
be provided in the SAP. 
 
9.7. 
STRATEGIES TO CONTROL TYPE I ERROR 
The overall type I error for the primary and key secondary endpoints is two-sided α=0.05. 
The fixed-sequence testing approach will be used to control the overall type I error rate at a two-sided 
0.05 level. If the primary endpoint is statistically significant at a two-sided 0.05 level, the first key 
secondary endpoint (ALP normalization) will be tested at the same level. If the first key secondary 
endpoint is statistically significant at a two-sided 0.05 level, the second key secondary endpoint (change 
in pruritus through week 24) will be tested at the same level. If the second key secondary endpoint is 
statistically significant at a two-sided 0.05 level, the third key secondary endpoint (change in pruritus 
through week 24) will be tested at the same level. 
Statistical testing for other secondary endpoints will be of exploratory nature. 
 

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9.8. 
SAMPLE SIZE CALCULATION 
All sample size calculations were done in East® 6.5. 
 
9.8.1. 
Reduction in ALP and TB 
The assumptions used for the determination of the sample size are: 
• 
An expected response rate in the placebo group slightly higher than that in the phase 3 pivotal 
study supporting the regulatory approval of OCA (10%) [4] 
• 
An expected response rates in the Elafibranor group at least similar to OCA (47%) 
The response rates from phase 3 pivotal study supporting the regulatory approval of OCA has been 
estimated after imputation of missing or non reliable data as non response. 
One hundred and fifty patients (100 elafibranor and 50 placebo) allow to achieve at least 90% power 
to demonstrate a statistically significant between group difference of 35% (47% in elafibranor group vs 
12% in placebo group) in the response rate at week 52 of the primary efficacy endpoint with a two-
sided alpha of 0.05 and using an exact Fisher test. 
 
9.8.2. 
Normalization in ALP 
Assuming 1/50 (2.0%) patient in the placebo arm with ALP normalization at week 52 (key secondary 
endpoint), 150 patients (100 elafibranor vs 50 placebo) provide at least 80% power to detect a 
statistically significant between group difference of 20.0% at a two-sided 0.05 alpha level. 
 
9.8.3. 
Change in pruritus 
Assuming a pooled SD of 2.3 points, 60 patients (40 elafibranor vs 20 placebo) with baseline PBC Worst 
Itch NRS score ≥4 provide at approximately 80% power to detect a statistically significant between 
group difference of 1.8 points in mean change from baseline in PBC Worst Itch NRS at a two-sided 0.05 
alpha level. It is assumed that the same assumptions would apply to the two key secondary endpoints 
for pruritus (through week 52 and through week 24). 
 
9.9. 
SAFETY ANALYSIS 
Safety data (exposure, AEs, clinical laboratory tests, vital signs, and ECGs) will be summarized by 
treatment group and overall using descriptive statistics after both DB period and LTE period. The main 
summaries of safety will be based on the SS. 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Descriptive statistics will be presented giving the number and percentage of patients reporting at least 
one AE, the number of events and the EAIR. In addition, comparison of treatment arms will be 
performed giving EAIR estimates and their CIs. An overall summary of AEs will be provided. 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. SAEs, AESIs, and AEs leading to discontinuation will also 
be summarized. Narratives will be written for all SAEs, AESIs, and AEs leading to discontinuation. 

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Clinical laboratory values (hematology, chemistry, and urinalysis) recorded at each timepoint and 
change from baseline will be summarized by treatment group and overall 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 52 weeks 
treatment period and end of DB 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 and overall. 
Vital signs recorded at each timepoint and change from baseline will be summarized by treatment group 
and overall using descriptive statistics. 
 
9.10. 
EXPLORATORY ANALYSIS (RELATED TO HISTOLOGICAL ASSESSEMENTS) 
Descriptive statistics on the histological scores and the non invasive markers of fibrosis (liver stiffness, 
ELF test and ProC3) will be provided by DB treatment groups and overall in the Exploratory (Histological) 
set.  
Change over time on the histological scores will be described using shift tables. In addition, the value 
at each visit as well as the change from baseline will be described on the non invasive markers of 
fibrosis. 
For assessing the correlation between the histological fibrosis endpoints (Nakanuma and Ishak scores) 
and the non invasive markers of fibrosis, the correlation coefficients and their CIs will be estimated 
depending on the nature and distribution of the endpoints considered. 
 
 
 

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10 
DATA HANDLING AND RECORD KEEPING 
10.1. DATA PROTECTION 
The contract between the sponsor and their vendors, and study sites specifies the responsibilities of the 
parties related to data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are secured by 
technical and organizational security measures designed to protect such data against accidental or 
unlawful loss, alteration, or unauthorized disclosure or access. 
In the event of a potential data security breach concerning personal data processed on behalf of the 
sponsor, the data protection officer must be informed without undue delay and no later than 24 hours 
from the discovery of the event. The data protection officer will evaluate the event and notify the Data 
Protection Authorities within 72 hours, if required. Corrective actions and preventive actions will be 
implemented to mitigate the possible adverse effects. Affected study participants will be informed 
accordingly. Ipsen Data Protection Officer can be contacted by email: dataprivacy@ipsen.com. 
 
10.2. CASE REPORT FORM AND SOURCE DOCUMENTS 
An eCRF 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 ICH Good Clinical Practice (GCP) guidance requirements. 
All study required patient data generated during the study will be recorded in the eCRF, with the 
exception of SAE forms which will be collected in paper. PRO data and central lab data will be transferred 
from electronic (source data) in the SDTM datasets. 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 
unique 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 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 drug, 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. 
 

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10.3. 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 IB, 
protocol/amendments, drug accountability records, sample informed consent, staff curriculum vitae, 
and 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 study drug. However, these documents should be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the Sponsor. All hospital 
records will be archived according to local regulation. 
The Sponsor should be notified if the Investigator relocates, retires, or for any reason withdraws from 
the study. The study 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, GCP (ICH topic E6 R2), applicable regulatory requirements, and the current Declaration of 
Helsinki and that valid data are entered into the eCRFs. 
To achieve this objective, the Study Monitor’s duties are to aid the Investigator and, at the same time, 
the Sponsor in the maintenance of attributable, legible, and contemporaneously recorded, original or a 
true copy, accurate (ALCOA), well-organized, and easily retrievable data. 
Before screening any patients in this study, the Study Monitor will review the protocol, the IB, the eCRFs 
and instructions for their completion and return, the procedure for obtaining informed consent, and all 
other study procedures (e.g. the laboratory manual, electronic patient-reported outcomes [ePRO] 
manual, IXRS manual, etc) including the reporting AEs, AESIs 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 study. 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, in accordance with relevant SOPs and GCP (ICH topic E6 R2) 
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.  
In cases of emergency (e.g., pandemic, political strife, natural disasters), to continue to ensure data 
monitoring, according to national regulations and under the responsibility of the Investigator, remote 
access to source documents can be provided to the Study Monitor to perfom remote Source Data 
Verification (SDV).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 
subjects) 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 and the GCP 
guidelines. 
This study also complies with applicable local regulatory requirements and laws of each country in which 
the study is performed, as well as any applicable guidelines. 

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11.3. QUALITY ASSURANCE 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory requirements, 
the Investigator should permit auditing by the Sponsor and/or designee and inspection by applicable 
regulatory authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to 
his/her study records for review, being understood that these personnel will adhere to all requirements 
for patient confidentiality, and as such will not disclose any personal identity or personal medical 
information. 
As soon as the Investigator is notified of a future inspection by the Authorities, he/she will inform the 
Sponsor and authorize the Sponsor to participate to this inspection if permitted by the Authorities. 
The confidentiality of the data verified and the anonymity of the patients should be respected during 
these inspections. 
The clinical study protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical study report, will be subject to independent Quality Assurance activities. Audits 
may be conducted at any time during or after the study to ensure the validity and integrity of the study 
data. 
 
 

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12 
ETHICS AND REGULATORY 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
The GCP guidelines and the US Code of Federal Regulations (CFR) Title 21 Section 56 (21 CFR 56) 
require that approval must be obtained from an 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 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/IEC’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 study. 
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 suspected unexpected serious adverse reactions (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 IRB/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 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 ICF 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 

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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. 
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 study drug. 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 local regulations, ICH guidelines, privacy and data protection requirements, 
where applicable, 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 and by the 
person who conducted the informed consent discussion prior to protocol-specific procedures being 
performed.  
A separate consent form will be obtained for optional biomarker samples to be collected and to be 
stored in the blood bank. 
Participants to the optional research biobanking programme have the right to withdraw their consent at 
any time and for any reason during the study or during the period of sample storage (i.e. the entire 15 
years during which samples are kept).  
If a participant wishes to withdraw their consent for optional biobanking and the samples are still at the 
investigator site or at the central laboratory at the time, the investigator must inform the study monitor 
in writing of the participant’s decision and destroy the samples. 
If the samples are at the sponsor’s repository (biobanking vendor), the investigator must inform the 
sponsor directly using the e-mail address: IpsenBiobanking@ipsen.com, mentioning only the participant 
ID in this e-mail. The sponsor will ensure destruction of the samples and all corresponding aliquots and 
issue confirmation of the destruction, which will be forwarded to the investigator. Analyses conducted 
before the withdrawal will not be affected. 
In addition separate consent forms will be obtained for optional liver biopsy sample collection, as well 
as for pregnant partner data collection. 
The Investigator must maintain the original, dated and signed ICFs. A copy of the signed ICFs 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 Clinical Trial Agreement (CTA). 
 

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12.5. DEFINITION OF THE END OF THE RESEARCH 
The end of the study is defined as completion of the last visit or procedure of the last patient 
participating in the study globally (last EOT DB/EOT LTE visit).  
 

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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. 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for one year after 
completion of the study. 
 
13.2. INSURANCE AND PATIENT INJURY 
The patients taking part in the study will be covered by the insurance taken by the Sponsor for this 
study, if they were to suffer any prejudice as a result of taking part in the study. 
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 study 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 study. 
 
 

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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 Sponsor will prepare an integrated Clinical Study Report (CSR). Prior to issuing the final CSR, the 
CRO will prepare a draft report for approval by the Sponsor and by the study Steering Committee. The 
draft report will be submitted for Quality Control, the findings of which will be incorporated into the final 
version. 
 
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 
IB, 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 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 CSR. The 
endorsement is required by some regulatory agencies. 
Furthermore, in the event that the study generates patentable results, the Investigator (or entity acting 
on his/her behalf according to local requirements) shall refrain from filing patent application(s) on such 
results, which will be filed by the Sponsor or its designees in its own name and at its expense. 
Protocol information and (final/interim) study results will be made publicly available on the US website 
(www.clinicaltrials.gov) and on the EU Clinical Trials Register (www.clinicaltrialsregister.eu) or EU 
Clinical Trials Portal (https://euclinicaltrials.eu/home). The sponsor also provides clinical trial information 
to other national clinical trial registries or databases according to local requirements/legislation. A lay 
summary 
of 
the 
study 
will 
be 
made 
available 
on 
the 
EU 
Clinical 
Trials 
Portal 
(https://euclinicaltrials.eu/home) and/or Sponsor website. 

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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 study results may be published or presented at scientific meetings after agreement between the 
Sponsor and the Investigators. 
If this is foreseen, the investigator should discuss specific publication concepts, including data to be 
covered, target congress/journal and proposed authors, with the Sponsor for agreement before 
initiation. 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. The investigator agrees to submit all manuscripts 
or abstracts to the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
 
 

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15 
REFERENCES LIST 
1 
Lammers, W.J., K.V. Kowdley, and H.R. van Buuren, Predicting outcome in primary biliary 
cirrhosis. Ann Hepatol, 2014. 13(4): p. 316-26. 
2 
Carbone, M., et al., The UK-PBC risk scores: Derivation and validation of a scoring system for 
long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology, 2016. 
63(3): p. 930-50. 
3 
Lammers, W.J., et al., Development and Validation of a Scoring System to Predict Outcomes of 
Patients 
With 
Primary 
Biliary 
Cirrhosis 
Receiving 
Ursodeoxycholic 
Acid 
Therapy. 
Gastroenterology, 2015. 149(7): p. 1804-1812 e4. 
4 
Nevens, F., et al., A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. 
New England Journal of Medicine, 2016. 375(7): p. 631-643. 
5 
Kuiper, E.M., 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(12): p. 1495-502. 
6 
Kumagi, T. and E.J. Heathcote, Primary biliary cirrhosis. Orphanet J Rare Dis, 2008. 3: p. 1. 
7 
Boonstra, K., U. Beuers, and C.Y. Ponsioen, Epidemiology of primary sclerosing cholangitis and 
primary biliary cirrhosis: a systematic review. J Hepatol, 2012. 56(5): p. 1181-8. 
8 
Kim, W.R., et al., Epidemiology and natural history of primary biliary cirrhosis in a US 
community. Gastroenterology, 2000. 119(6): p. 1631-6. 
9 
Al-Harthy, N. and T. Kumagi, Natural history and management of primary biliary cirrhosis. Hepat 
Med, 2012. 4: p. 61-71. 
10 
Selmi, C., et al., Environmental pathways to autoimmune diseases: the cases of primary biliary 
cirrhosis and multiple sclerosis. Arch Med Sci, 2011. 7(3): p. 368-80. 
11 
Ali, A., T. Byrne, and K. Lindor, Orphan drugs in development for primary biliary cirrhosis: 
challenges and progress. 2015. 5: p. 83-97. 
12 
Hirschfield, G.M. and M.E. Gershwin, The immunobiology and pathophysiology of primary biliary 
cirrhosis. Annu Rev Pathol, 2013. 8: p. 303-30. 
13 
Beuers, U. and K.D. Lindor, A major step towards effective treatment evaluation in primary 
biliary cirrhosis. J Hepatol, 2011. 55(6): p. 1178-80. 
14 
Carbone, M., et al., Sex and age are determinants of the clinical phenotype of primary biliary 
cirrhosis and response to ursodeoxycholic acid. Gastroenterology, 2013. 144(3): p. 560-569 e7; 
quiz e13-4. 
15 
Lammers, W.J., et al., Levels of alkaline phosphatase and bilirubin are surrogate end points of 
outcomes of patients with primary biliary cirrhosis: an international follow-up study. 
Gastroenterology, 2014. 147(6): p. 1338-49 e5; quiz e15. 
16 
Giannini, E.G., R. Testa, and V. Savarino, Liver enzyme alteration: a guide for clinicians. CMAJ, 
2005. 172(3): p. 367-79. 
17 
Crosignani, A., et al., Clinical features and management of primary biliary cirrhosis. World J 
Gastroenterol, 2008. 14(21): p. 3313-27. 
18 
Corpechot, C., et al., Biochemical response to ursodeoxycholic acid and long-term prognosis in 
primary biliary cirrhosis. Hepatology, 2008. 48(3): p. 871-7. 
19 
Lindor, K.D., et al., Primary biliary cirrhosis. Hepatology, 2009. 50(1): p. 291-308. 
20 
EASL, EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol, 
2009. 51(2): p. 237-67. 
21 
Corpechot, C., et al., A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. 
New England Journal of Medicine, 2018. 378(23): p. 2171-2181. 
22 
Ghonem, N.S., D.N. Assis, and J.L. Boyer, Fibrates and cholestasis. Hepatology, 2015. 62(2): p. 
635-43. 
23 
Cattley, R., et al., Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard 
to Humans? Regulatory Toxicology and Pharmacology, 1998. 27(1): p. 47-60. 
24 
Corpechot et al Noninvasive Elastography-Based Assessment of Liver Fibrosis Progression and 
Prognosis in Primary Biliary Cirrhosis. Hepatology 2012; 56 (1). p 198-212. 

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25 
Murillo Perez, C.F., et al., Goals of Treatment for Improved Survival in Primary Biliary 
Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization 
of Alkaline Phosphatase. Am J Gastroenterol, 2020. 
26 
Pickering, T.G., et al., Recommendations for blood pressure measurement in humans and 
experimental animals: part 1: blood pressure measurement in humans: a statement for 
professionals from the Subcommittee of Professional and Public Education of the American 
Heart Association Council on High Blood Pressure Research. Circulation, 2005. 111(5): p. 697-
716. 
27 
Elman, S., et al., The 5-D itch scale: a new measure of pruritus. Br J Dermatol, 2010. 162(3): 
p. 587-93. 
28 
Jacoby, A., et al., Development, validation, and evaluation of the PBC-40, a disease specific 
health related quality of life measure for primary biliary cirrhosis. Gut, 2005. 54(11): p. 1622-
9. 
29 
Broderick, J.E., et al., Pittsburgh and Epworth sleep scale items: accuracy of ratings across 
different reporting periods. Behav Sleep Med, 2013. 11(3): p. 173-88. 
30 
Johns, M.W., A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep, 1991. 14(6): p. 540-5. 
31 
Chalasani, N. and A. Regev, Drug-Induced Liver Injury in Patients With Preexisting Chronic Liver 
Disease in Drug Development: How to Identify and Manage? Gastroenterology, 2016. 151(6): 
p. 1046-1051. 
32 
Regev, A., et al., Consensus: guidelines: best practices for detection, assessment and 
management of suspected acute drug-induced liver injury during clinical trials in patients with 
nonalcoholic steatohepatitis. Aliment Pharmacol Ther, 2019. 49(6): p. 702-713. 
33 
CTFG, Recommendations related to contraception and pregnancy testing in clinical trials. 
Available 
at:https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Version_1.
1_updated.pdf. 
 

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16 
APPENDICES: 
16.1. APPENDIX 1: ALCOHOL COMPARISON TABLE 
Alcohol 
type 
Alcohol by 
volume (ABV) 
Volume 
Amount of alcohol 
Fluid ounce 
mL 
Units  
Grams 
Beer 
3.5% 
12 
350 
0.7 
9.8 
Beer 
5% 
12 
350 
1 
14 
Cider 
7% 
12 
350 
1.4 
19.6 
Distilled 
spirits or 
liquor  
40% 
1.5 
45 
1 
14 
Wine 
12% 
5 
150 
1 
14 
Footnote: 
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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16.3. APPENDIX 3: SAMPLE PATIENT REPORTED OUTCOME QUESTIONNAIRES: 
16.3.1. 
PBC-40 
 

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16.3.2. 
Epworth Sleepiness Scale (ESS) 
  
 

 
 
 
 
 
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16.3.3. 
5-D Itch Scale 
 
 
 

 
 
 
 
 
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16.3.4. 
PROMIS Fatigue Short Form 7a 
 
 
 
 
 

 
 
 
 
 
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16.3.5. 
The Patient Global Impression of Change (PGIC) 
  
 
 

 
 
 
 
 
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16.3.6. 
The Patient Global Impression of Severity (PGIS) 
  
 
 

 
 
 
 
 
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16.3.7. 
PBC Worst Itch NRS 
 
PBC Worst Itch NRS 
 
 
PBC Worst Itch NRS-Past Week 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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16.3.8. 
EuroQoL EQ-5D-5L 
 
 

 
 
 
 
 
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