Conditions: Non-Alcoholic Steatohepatitis (NASH)
Keywords: Non-Alcoholic Steatohepatitis NASH peroxisome proliferator-activated receptor (PPAR) Liver Diseases Fibrosis Fatty Liver Non-alcoholic Fatty Liver Disease Digestive System Diseases IVA337
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 247
Healthy volunteers: no

Brief summary:
Non-alcoholic steatohepatitis, abbreviated as NASH, is a chronic liver disease that may progress to cirrhosis. The disease is mostly associated with obesity and type 2 diabetes mellitus, or insulin resistance and is very common. However, Treatment of NASH is a significant unmet clinical need.

IVA337 (lanifibranor) is a next generation pan-PPAR (peroxisome proliferator-activated receptors) agonist addressing the pathophysiology of NASH : metabolic, inflammatory and fibrotic.

The purpose of this research is to evaluate the efficacy and the safety of two doses of IVA337 (800mg, 1200 mg) per day for 24 weeks versus placebo in adult NASH patients with liver steatosis and moderate to severe necroinflammation without cirrhosis.

Detailed description:
Randomized (stratified on diabetes), placebo-controlled, double-blind, parallel-assignment, dose-range multicenter study

There are 3 parallel treatment groups: placebo, IVA337 800mg once a day (Quaque Die, QD) and IVA337 1200mg QD (identical tablets of 400mg IVA337 or placebo). Both, patient and investigator are blinded.

For each patient, the study duration will be an overall of 6 to 8 months (with a 10-day to 4-week selection period, a 24-week treatment period and a 4-week follow-up period).

Arms:
arm 1: IVA337 400mg, once a day (Quaque Die, QD) with food arm 2: IVA337 400mg, once a day (Quaque Die, QD) with food arm 3: Placebo to match, once a day (Quaque Die, QD) with food

Interventions: intervention 1: IVA337 intervention 2: IVA337 intervention 3: Placebo
Intervention descriptions: intervention 1: 1200mg intervention 2: 800mg intervention 3: Placebo to match

Protocol document:
Prot_002.pdf: 
Confidentiality statement 
This information may not be used, published, or otherwise disclosed without the prior written 
authorization from the Sponsor. 
 
 
 
STUDY PROTOCOL 
 
Protocol identification: IVA_01_337_HNAS_16_002 
EudraCT number: 2016-001979-70 
Version 5.0 – July 09th, 2019 
 
Study title 
A randomized, double-blind, placebo-controlled, multicenter, 
dose-range, proof-of-concept, 24-week treatment study of IVA337 in 
adult subjects with nonalcoholic steatohepatitis (NASH) 
Investigational medicinal product: IVA337 (lanifibranor) 
 
Development phase: IIb 
Study initiation date: Q1 2017 
Study completion date (expected): 2020 
 
Principal Investigators: Sven Francque, MD, PhD, Division of Gastroenterology and 
Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 
Edegem, Belgium 
 
Manal F. Abdelmalek, MD, MPH, Professor of Medicine, NAFLD 
Clinical Research Program, Division of Gastroenterology / 
Hepatology, Duke University, 40 Duke Medicine Circle, Clinic 2H / 
2J, Durham, NC 27710, USA 
Sponsor: 
Inventiva S.A., 50 rue de DIJON, 21121 Daix, France 
Sponsor Chief Medical Officer: 
Marie-Paule Richard, MD 
 
 








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Signature page  
Study title: A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-
of-concept, 24-week treatment study of IVA337 in adult subjects with nonalcoholic steatohepatitis 
(NASH).  
Study code: IVA_01_337_HNAS_16_002. 
Sponsor and Investigator have approved the protocol Version 5.0, (July 09th, 2019), and confirm 
hereby to perform this study in compliance with this protocol or an approved amendment, the 
current Helsinki Declaration (Appendix A), GCP and applicable regulatory requirements. 
 
INVESTIGATOR REPRESENTATIVES 
Sven Francque, MD, PhD 
Principal Investigator, 
Antwerp 
Date 
Signature : 
 
 
Manal F. Abdelmalek, MD, 
MPH 
Principal Investigator, 
Durham 
Date 
Signature : 
 
 
 
SPONSOR REPRESENTATIVES (Inventiva Pharma) 
Marie-Paule Richard, MD 
Chief Medical Officer  
Date 
Signature : 
 
 
Martine Baudin, MD 
Clinical Research Physician 
Date  
Signature : 
 
Philippe Huot-Marchand 
Head of Biometry 
Date 
Signature :  
 
 
Annie-Claude Benichou, MD 
Chief Executive Officer, 
Stragen, Pharmacovigilance 
Date: 19-JUL-2019 
Signature : 
 
 
 
 


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Revision history 
Version 
Date 
Main Revision summary 
Version 1.0 
June 28th, 2016 
Initial version 
Version 1.1 
August 19th, 2016 
Pregnancy 
test 
and 
IMP 
hypersensitivity 
inclusion/exclusion criteria update. 
Add of “non treatment-emergent AE” definition. 
“End of trial” definition update 
Version 1.2 
(France only) 
January 5th, 2017 
Addition of CPK and osteopenia as exclusion 
criteria 
Version 1.2 
(Switzerland 
only) 
February 10th, 2017 
Inclusion criteria 8 update (Contraceptive 
method) 
Version 1.2 
(Germany only) 
February 10th, 2017 
Inclusion criteria 9 update 
Version 1.3 
(Switzerland 
only) 
 
Recruitment period update 
Version 2.0 
March 2nd, 2016 
Update inclusion/exclusion criteria list with all 
country specific requests 
Version 3.0 
August 3rd, 2017 
Recruitment period update 
Version 4.0 
November 2nd, 2017 
Add pre-treatment liver biopsy as screening 
procedure when no biopsy performed less than 6 
months before screening is available 
Update of study screening procedures (including 
Liver MultiScan in selected sites) 
Version 4.1 
September 14th, 2018 
Adding sites in the US, minor update of a few 
inclusion/non-inclusion criteria, corrections of 
typo errors and adaptation to US sites. Version 
applicable for US only. 
Version 4.2 
December 12th, 2018 
Adding urine dipstick, to be performed on site, at 
each visit when a urine sample is collected. 
Version 5.0 
July 09th, 2019 
Updating the secondary endpoints, safety and 
biomarkers analysis performed, clarification of 
some 
inclusion 
/ 
exclusion 
parameters, 
clarification 
of 
prohibited 
concomitant 
medications (i.e. dosages, routes, washout period 
if relevant). 
 
 


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Synopsis 
Study title: A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-of-
concept, 24-week treatment study of IVA337 in adult subjects with nonalcoholic steatohepatitis 
(NASH).  
Study code: IVA_01_337_HNAS_16_002. 
Trial registration: 2016-001979-70 
Protocol version and date: Version 5.0, (July 09th, 2019) 
Development phase: IIb, Proof of Concept 
Investigators & study location: Principal Investigators: Pr. Sven Francque, Antwerp University 
Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium.; Pr. Manal F. Abdelmalek, MD, MPH, 
Division of Gastroenterology / Hepatology, Duke University, 40 Duke Medicine Circle, Clinic 
2H / 2J, Durham, NC 27710, USA. 
Multi-center, at least 60 sites across Europe, United States of America (USA) and other 
countries worldwide (incl. Canada, Australia and Republic of Mauritius). 
Studied period: First enrolment: Q1 2017. Expected completion date: 2020. 
Objectives: To assess the safety and the efficacy on the activity part of the Steatosis Activity 
Fibrosis (SAF) histological score (inflammation and ballooning) of a 24-week treatment with 
two doses of lanifibranor (800, 1200 mg/24h) in NASH adult patients. 
Study design: Randomized (stratified on diabetes), placebo-controlled, double-blind, parallel-
assignment, dose-range multicenter study. 
Study duration: For each patient, the study duration will be an overall of 6 to 8 months (with a 3-day 
to 4-week selection period, a 24-week treatment period and a 4-week follow-up period).  
Total number of subjects:  
At least 300 patients will be screened, to randomize 225 patients (75 patients/arm).  
Diagnosis and main criteria for inclusion: 
 Adult subjects, age ≥18 years. 
 NASH histological diagnosis according to the currently accepted definition of both 
EASL and AASLD, requiring the combined presence of steatosis (any degree ≥ 5%) 
+ lobular inflammation of any degree + liver cell ballooning of any amount, on a liver 
biopsy performed ≤ 6 months before screening in the study or at screening, and 
confirmed by central reading during the screening period and 
a. SAF Activity score of 3 or 4 (>2) 
b. SAF Steatosis score ≥ 1  
c. SAF Fibrosis score < 4 
 Subject agrees to have a liver biopsy performed after 24 weeks of treatment. 
 Compensated liver disease with the following hematologic and biochemical criteria 
before randomization: 
o ALT < 10xULN 


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o Hemoglobin ≥ 110 g/L (11g/dL) for females and ≥ 120 g/L (12g/dL) for 
males 
o White blood cell (WBC) > 2.5 10^9/L (2.5 10^3/µL) 
o Neutrophil count > 1.5 10^9/L (1.5 10^3/µL) 
o Platelets > 100 10^9/L (100 10^3/µL) 
o Total bilirubin < 35 µmol/L (2.06 mg/dL). Patients with bilirubin ≥ 35 
µmol/L (2.06 mg/dL) can be included if non-conjugated bilirubin in the 
setting of a Gilbert’s syndrome. 
o Albumin > 36 g/L (3.6 g/dL) 
o International Normalized Ratio (INR) < 1.4 
o Serum creatinin < 115 µmol/L (1.3 mg/dL) (men) or < 97 µmol/L               
(1.1 mg/dL) (women) or estimated glomerular filtration rate ≥ 60 
mL/min/1.73m2 
 No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, 
HBV,  HCV, Wilson’s, α-1-antitrypsin deficiency, hemochromatosis, etc…), considered 
to have an impact on the patient’s safety or on the efficacy evaluation. 
 If applicable, have a stable type 2 diabetes, defined as HbA1c ≤ 8.5% and fasting 
glycemia <10 mmol/L (180 mg/dL), no introduction of new medication in the 
previous 6 months, and no new symptoms associated with decompensated diabetes in 
the previous 3 months. Minor modifications of anti-diabetic treatments or dosages are 
allowed if done in a context of stable type 2 diabetes, i.e. HbA1c ≤ 8.5% in the 
previous 6 months. 
 Have a stable weight since the liver biopsy was performed, defined by no more than 
a 5% loss of initial body weight. 
 Negative pregnancy test or post-menopausal. Women with childbearing potential (i.e. 
fertile, following menarche and until becoming post-menopausal unless permanently 
sterile) must be using a highly effective method of contraception (i.e. combined 
(estrogen and progestogen containing) hormonal/ progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner). The 
contraceptive method will have to be followed for at least one menstruation cycle after 
the end of the study. 
 Subjects having given her/his written informed consent. 
Exclusion criteria: 
 Evidence of another form of liver disease, considered to have an impact on the 
patient’s safety or on the efficacy evaluation. 
 History of sustained excess alcohol ingestion in the year before the pre-study 
treatment biopsy: daily alcohol consumption > 30 g/day (3 drinks per day) for males 
and > 20 g/day (2 drinks per day) for females. 


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 Unstable metabolic condition: Weight change > 5% in the last three months, diabetes 
with poor glycemic control (HbA1c > 8.5%), introduction of an antidiabetic or of an 
anti-obesity drug or restrictive bariatric (weight loss) surgery in the past 6 months 
prior to screening. 
 History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or 
ingestion of drugs known to produce hepatic steatosis including oral corticosteroids 
(at dose >5mg/day prednisone equivalent), estrogens (at doses greater than those used 
for contraception or hormone replacement), tamoxifen, methotrexate, tetracycline or 
amiodarone in the previous 6 months. Corticosteroids administered by routes other 
than oral are allowed. One short (<2 weeks) course of oral corticosteroids, more than 
3 months before the pre-study treatment biopsy is also allowed. 
 Significant systemic or major illnesses other than liver disease, including congestive 
heart failure (class C and D of the AHA), unstable coronary artery disease, 
cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, 
serious psychiatric disease, malignancy that, in the opinion of the Investigator, would 
preclude treatment with lanifibranor and/or adequate follow up. 
 HBs antigen >0, HCV PCR >0 (patients with a history of HCV infection can be 
included if HCV PCR is negative since more than 3 years), HIV infection. 
 Pregnancy or lactation or inability to adhere to adequate contraception in women of 
child-bearing potential. 
 Active malignancy except cutaneous basocellular carcinoma. 
 Any other condition, which, in the opinion of the Investigator would impede 
competence or compliance or possibly hinder completion of the study. 
 Body mass index (BMI) >45 kg/m2. 
 Type 1 diabetes and type 2 diabetic patient on insulin. 
 Diabetic ketoacidosis.  
 Fasting Triglycerides > 300 mg/dL (3.39 mmol/L). 
 Hemostasis disorders or current treatment with anticoagulants. 
 Contra-indication to liver biopsy. 
 History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease 
event, including myocardial infarction, except patients with only well controlled 
hypertension. Any clinically significant ECG abnormality reported by central ECG 
reading, confirmed by the Investigator to be Clinically Significant. 
 Participation in any other investigational drug study within the previous 3 months. 
 Have a known hypersensitivity to any of the ingredients or excipients of the IMP 
including: Lactose monohydrate, Hypromellose, Sodium laurilsulfate, Sodium starch 
glycolate (type A), Magnesium stearate, Opadry™ II 85F18422  
 Be possibly dependent on the Investigator or the Sponsor (e.g., including, but not 
limited to, affiliated employee). 
 Creatine phosphokinase (CPK) >5 x ULN. 


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 Patient with history of well-documented osteopenia. Patient treated with vitamin D 
and/or Calcium based supplements for preventive reasons can be included. 
(The criteria below are applicable only for patients who will undergo a MRI/LMS in selected 
centers) 
 Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. 
Sedation is permitted at discretion of Investigator. 
 Metallic implant of any sort that prevents MRI examination including, but not limited 
to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural 
stimulator, metallic contraceptive device, tattoo, body piercing that cannot be 
removed, cochlear implant; or any other contraindication to MRI examination. 
Test product, dose and mode of administration: 
Tablets of lanifibranor 400 mg, two doses of lanifibranor (800 and 1200 mg QD), i.e. 3 tablets 
of 400 mg/placebo per os, during breakfast, once daily (QD) will be evaluated. 
Prohibited concomitant medications:  
If not specified, the following treatment must be stopped at the latest before randomization. 
 PPAR Gamma agonists, PPAR Alpha agonists (fibrates), ezetimibe,  
 Bile salts chelators, Phytosterols, fish oils, 
 Glucagon like peptide-1 receptor agonists (incl. liraglutide, exenatide), 
 Insulin, 
 Vitamins E (alpha-tocopherol), 
 Anticoagulants (incl. warfarin, dabigatran, rivaroxaban, apixaban), 
 Oral corticosteroids. 
 
Allowable medications for standard care or precautions: 
 Obesity: stable weight since the liver biopsy was performed, defined by no more than a 
5 % loss of initial body weight (see inclusion criteria 7). 
 Treatment used for the underlying medical condition 
Treatments are allowed within certain restrictions (described above and below) and 
provided that they have been kept at stable doses for at least 6 months before the pre-
treatment biopsy. 
Type 2 diabetes:  
 Metformin,  
 Dipeptidyl peptidase-4 inhibitors,  
 Sodium-glucose transport protein 2 inhibitors: canagliflozin, dapagliflozin 
and empagliflozin.  
Minor modifications of anti-diabetic treatments or dosages are allowed if done in the context of 
stable type 2 diabetes, i.e. HbA1c ≤ 8.5% in the previous 6 months. 
 
Hyperlipidemia: only statins at stable doses within the past 3 months before pre-study 
treatment biopsy will be allowed. 
Antiplatelets agents: The antiplatelets agents (incl. low-dose aspirin, ticlopidine, 
clopidogrel, prasugrel, ticagrelor) are allowed. 


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Herbal supplements and Others Supplementation: Herbal preparations or vitamin 
supplements with no exact composition known should not be started during the 
course of the study as they could be liver toxic. 
 Other Medications  
Medications other than the IMP and those mentioned above should only be started 
during the course of the study with the agreement of the Investigator in order to avoid 
interference with study assessments. The need for other medication may lead to the 
exclusion of the patient from the study.  
If a symptomatic medication is needed to treat adverse events related to IMP, the 
Investigator will inform the Sponsor about the concomitant medication given. 
Duration of treatment: IMP will be given for 24 weeks. 
Parameters assessed during the study: Continuous recording of adverse events and 
concomitants therapies, physical examination, vital signs, ECG (12-leads), haematology, 
blood biochemistry and urinalysis, liver enzymes, QOL questionnaires including the Flinders 
Fatigue scale (FFS) and the SF-36v2 health survey, Transient Elastography (TE) (mandatory 
before the liver biopsy, when performed at screening) and Controlled Attenuation Parameter 
(CAP), central reading of liver biopsies, biobank for specific markers of inflammation, 
lipids, glucids, fibrosis, bone remodeling and lanifibranor plasma trough levels and only at 
screening in selected sites Magnetic Resonance Imaging (MRI) /Liver MultiScan (LMS) 
measuring Liver Inflammation and Fibrosis (LIF) score and hepatic fat content MRI-PDFF 
(proton density fat fraction). 
Primary efficacy criterion: SAF activity score, i.e. the addition of hepatocyte ballooning score 
(0 to 2) and lobular inflammation score (0 to 2). Assessment of the difference between any 
verum groups versus placebo. 
Statistical methods and Safety: 
Sample size: The expected rate of responders (decrease of 2 points of SAF activity score) was 
estimated to 10% in the placebo group by a panel of clinical expert. An excess rate of 
responders of 20% was assessed beyond any doubt as clinically pertinent since the chance 
of being responder is three time larger in the best dose and the Number Needed to Treat 
(NNT) is as low as 5. The sample required to reach a power of at least 80% is 72 patients per 
group with a two-sided alpha of 0.025 (adjustment for multiplicity) and has been rounded to 
75. Consequently, 225 patients will be randomized. 
Randomization: Patients will be randomized 1:1:1 (Placebo, 800 mg lanifibranor, 1200 mg 
lanifibranor) and stratified on presence/absence of type 2 diabetes to receive either dose of 
lanifibranor or a matching placebo. 
Safety variables: The review of safety and tolerance will be performed on the safety population. 
The safety analysis will be based on the reported AEs and other safety information. The 
effect of the demographic differences (gender, age, etc.) and risk factors of clinical relevance 
will be explored.  
Efficacy variables: 
Primary endpoint: The primary endpoint is a binary outcome (responder / non responder). A 
responder is defined as a decrease from baseline to week 24 of at least 2 points of the SAF 
activity score combining hepatocellular inflammatory and ballooning score without fibrosis 


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progression. Responder rates will be compared between the placebo and IMP groups at the 
end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on 
diabetes. 
Secondary endpoints:  
The following changes from baseline to 24 weeks of treatment will be evaluated: 
 NASH improvers defined as subjects with a decrease of at least 2 points in NAS, and 
no worsening in fibrosis from baseline to end of treatment (week 24).  
 Percent of patients with resolution of NASH (Steatosis without ballooning and with or 
without mild inflammation) and no worsening of fibrosis) from baseline to end of 
treatment (week 24). 
 Percent of patients with a change in components of SAF score from baseline to end of 
treatment (week 24): 
- 
Steatosis: -1 point 
- 
Lobular inflammation: -1 point 
- 
Ballooning: -1 point 
 Percent of patients with at least 1- point improvement of fibrosis score on a 4-point 
scale (SAF) without worsening of NASH, defined as no increase for ballooning, or 
inflammation, or steatosis, using the SAF scoring system, from baseline to end of 
treatment (week 24). 
 Change in fibrosis score on a 4-points scale (SAF) and modified Ishak: - 1 point from 
baseline to end of treatment (week 24).  
 Liver enzymes (ALT, AST, γGT) change from baseline to end of treatment (week 24). 
 Inflammatory markers (fibrinogen, hs-CRP, alpha2 macroglobulin and haptoglobin 
levels) change from baseline to end of treatment (week 24). 
 Glucose metabolism (fasting glucose and insulin, HOMA index and, in subjects with 
T2DM, HbA1c) change from baseline to end of treatment (week 24). 
 Main plasma lipids levels (TC, HDL-C, calculated LDL-C, TG and apoA1) change 
from baseline to end of treatment (week 24). 
 Adiponectin change from baseline to end of treatment (week 24). 
Exploratory endpoints:  
 Specific markers of inflammation, lipids, glucids, fibrosis, bone remodeling change 
from baseline to end of treatment (week 24).  
 Transient Elastography (TE) and Controlled Attenuation Parameter (CAP) change 
from baseline to end of treatment (week 24) 
 If deemed necessary: Immunohistochemistry: change in the semiquantitative score of 
ballooning and stellate cell activation from baseline to end of treatment (week 24).  
The Hochberg procedure will be applied to take into account multiplicity of testing (no 
adjustment for safety parameters). Adjustment for multiplicity will be done for the two 
treatment group comparisons (high dose vs placebo and low dose vs placebo) but not for the 
number of studied parameters. 


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Pharmacokinetic variables: Trough plasma levels of lanifibranor will be assessed at V1 (week 
4) and V3 (week 24). 
Study procedures: 
For the patients with a liver biopsy performed within 6 months before screening, all 
diagnosis tests regarding the elimination of other causes of liver disease should have been 
performed before the patient is considered for inclusion in the study as part of the routine 
medical care and will not be performed specifically for the study. 
For the patients without a liver biopsy performed within 6 months before screening, the 
screening phase will be done in successive steps to avoid unnecessary biopsy:  
Step 1: Review of the medical history, concomitant medications, physical examination, 
electrocardiogram, biological sampling and FibroScan (mandatory). Patients will 
be withdrawn from the study at this step in case of TE > 12.5 kPa (i.e. high 
probability of cirrhosis). 
Step 2: MR/Liver MultiScan technology, only in selected sites. Patients will be withdrawn 
from the study at this step in case of LIF < 2 or MRI-PDFF 5%. 
Step 3: A liver biopsy will be performed. In all cases, liver biopsy will be performed upon 
medical indication and according to the standard practice of the site. 
After validation of the histological criteria by the central reading assessment, patients can 
be randomized. 
All patients will undergo six visits, screening V-1 (-8 weeks to -2 weeks), randomization 
V0 (week 0), interim V1 (week 4), interim V2 (week 14), end-of-treatment V3 (week 24) 
and follow-up V4 (4 weeks after end-of-treatment). For all visits except for screening, time 
windows are defined up to +/- 3 days compared to V0 and are indicated in the Table 1 and 
Table 2. The screening visit time window is of 2 to 4 weeks before V0 when slides from a 
biopsy performed within the past 6 months are available, and of 2 to 8 weeks when the pre-
treatment biopsy is part of the screening procedures. 
Patients will be randomized to either dose of lanifibranor or placebo at V0 and treated for 
24 weeks until V3. 
A physical examination will be performed at each visit. An ECG will be done at 
screening, V1 and V3. Adverse events and concomitant medications will be recorded 
throughout the study. 
A liver biopsy will be performed at V3. 
The laboratory assessments performed at screening and end-of-treatment will include: 
haematology (CBC), blood biochemistry (ALT, AST, γGT, alkaline phosphatase, total 
bilirubin, conjugated bilirubin, ultra-sensitive CRP, total cholesterol, triglycerides, HDL 
cholesterol, LDL cholesterol, creatinine, fasting glucose, insulin, HgbA1c, albumin, CPK, 
sodium, potassium, calcium), and two serum bank samples. 
Urine Samples will be collected at V0 (including urine pregnancy test), V2, V3 and V4. 
Urine analysis by dipstick evaluating hematuria will be done on site. Urine samples will then 
be stored for further assessment and/or for safety evaluation. 
Trough plasma levels of lanifibranor will be assessed at V1 and V3. 
 
 


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Figure 1: NATIVE Study Design and Screening process 
 
 
 
 


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Table 1: Study Schedule of procedures (if a liver biopsy of less than 6 months is available 
before screening) 
Study Period 
Screening 
Treatment 
Follow up 
Visit 
V-1 
V0 
V1 
V2 
V3 
V4 
Weeks (target+/-3days, referred to V0) 
-4 to -2 
0 
4 
14 
24 
28 
Informed consent 
X 
  
  
  
  
  
Inclusion/exclusion criteria 
X 
X 
  
  
  
  
Demographics, Medical history 
X 
  
  
  
  
  
Alcohol consumption 
X 
X 
X 
X 
X 
X 
Physical examination/ 
vital signs: 
height (inclusion only), weight, waist circumference, SBP, 
DBP, HR 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiogram 
X 
  
X 
  
X 
  
Pregnancy test ((a): Blood test, HCG; (b): Urine Test) 
X(a) 
X(b) 
  
  
  
  
HIV serology 
  
X 
  
  
  
  
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
Quality of life questionnaires 
  
X 
  
  
X 
  
Urine Samples 
  
X 
  
X 
X 
X 
Blood Samples 
X 
X 
X 
X 
X 
X 
FibroScan™ (if available)  
X 
 
 
 
X 
 
Central Reading of liver biopsy to confirm NASH diagnosis 
X 
  
  
  
  
  
Liver biopsy at end of treatment 
  
  
  
  
X 
  
Primary efficacy evaluation: Inflammation and ballooning SAF 
X(c) 
  
  
  
X 
  
Secondary efficacy evaluation 
  
  
  
  
  
  
NAS score and other liver histology indices  
X 
  
  
  
X 
  
Inflammatory markers 
fibrinogen, hs-CRP, alpha2-macroglobulin, haptoglobin 
levels 
  
X 
  
  
X 
  
Glucose metabolism 
fasting glucose and in subjects with T2DM: HbA1c 
X 
X 
X 
X 
X 
X 
Insulin, HOMA, Peptide C, Fructosamine 
  
X 
  
  
X 
  
Lipids 
Lipids: TC, HDL-C, calculated LDL-C and TG 
X 
X 
X 
X 
X 
X 
FFA, adiponectin, Leptin and apoA1 
  
X 
  
  
X 
  
Chemistry 
Plasma Iron, Transferrin, Ferritin 
X 
  
  
  
X 
  
Fibrosis markers 
TIMP-1, TIMP-2, Cytokeratin K18, hyaluronic acid, P3NP, 
FGF 21  
  
X 
  
  
X 
  
Exploratory criteria Biobank 
  
  
  
  
  
  
Other biomarkers 
IL-6, IL-13, IL-17A, IL1B, TNF-a, INFg, APO B, APO C3, 
MMP2, MMP9, ProC3 (non-exhaustive list) 
  
X 
  
  
X 
  
Genotype 
PNPLA3, TM6FS2  
  
X(d) 
  
  
  
  
Safety assessments 
  
  
  
  
  
  
Hematology 
WBC (+diff. Count), RBC, hemoglobin, MCV, hematocrit, 
Platelets, reticulocytes, CCMH, Hematocrit 
X 
X 
X 
X 
X 
X 
Inflammatory markers 
Nt-ProBNP 
  
X 
  
  
X 
  
Chemistry 
creatinine, urea, albumin, CPK 
X 
X 
X 
X 
X 
X 
Liver tests  
AST, ALT, ALP, GGT, total bilirubin 
X 
X 
X 
X 
X 
X 
Bone 
B-Crosslaps, Osteocalcin 
  
X 
  
  
X 
  
Coagulation factors 
INR 
X 
X 
X 
X 
X 
X 
Urine dipstick 
Hematuria 
 
X 
 
X 
X 
X 
Pharmacokinetics: IVA337 (+ metabolites) trough sampling 
  
  
X 
  
X 
  
Adverse events 
  
X 
X 
X 
X 
X 
Dispense study treatment 
  
X 
X 
X 
  
  
Compliance check 
  
  
X 
X 
X 
  
(c) Central reading on biopsy within the 6 months prior to screening to confirm NASH diagnosis;  
(d) Only for patients having consent for genetic testing; 
 
 


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Table 2: Study Schedule of procedures (if a liver biopsy is NOT available before screening) 
Study Period  
 
Screening 
 
Treatment 
Follow 
up 
Visit 
V-1 
V0 
V1 
V2 
V3 
V4 
Weeks (target +/- 3 days, referred to V0) 
-8 to -4 
0 
4 
14 
24 
28 
Screening Step 
1 
2 
3 
 
 
Informed consent 
X  
 
 
  
  
  
  
  
Inclusion/exclusion criteria 
X  
 
 
X 
  
  
  
  
Demographics, Medical history 
X 
 
 
  
  
  
  
  
Alcohol consumption 
X 
 
 
X 
X 
X 
X 
X 
Physical examination/ 
vital signs: 
height (inclusion only), weight, waist circumference,  
SBP, DBP, HR 
X 
 
 
X 
X 
X 
X 
X 
12-lead Electrocardiogram 
X 
 
 
  
X 
  
X 
  
Pregnancy test ( Blood test, HCG) 
X 
 
X(a) 
 
  
  
  
  
Pregnancy test (Urine Test) 
 
 
 
X 
 
 
 
 
HIV serology 
  
X 
 
 
  
  
  
  
  
Concomitant medications 
X 
 
 
X 
X 
X 
X 
X 
Quality of life questionnaires 
 
 
  
X 
  
  
X 
  
Urine Samples 
 
 
  
X 
  
X 
X 
X 
Blood Samples 
X  
 
X(a) 
X 
X 
X 
X 
X 
LiverMultiScan/ Magnetic Resonance (in selected sites) 
 
X(b)  
 
 
 
 
 
 
FibroScan™  
X 
 
 
 
 
 
X 
 
Liver biopsy 
 
 
X(c) 
 
 
 
X 
  
Primary efficacy evaluation: Inflammation and ballooning SAF 
 
 
X 
 
 
 
X 
  
Secondary efficacy evaluation 
 
 
  
  
  
  
  
  
NAS score and other liver histology indices  
 
 
X 
  
  
  
X 
  
Inflammatory markers 
 fibrinogen, hs-CRP, alpha2-macroglobulin, haptoglobin 
levels 
 
 
  
X 
  
  
X 
  
Glucose metabolism 
 fasting glucose and in subjects with T2DM: HbA1c 
X 
 
X(a) 
X 
X 
X 
X 
X 
Insulin, HOMA, Peptide C, Fructosamine 
 
 
 
X 
  
  
X 
  
Lipids 
Lipids: TC, HDL-C, calculated LDL-C and TG 
X  
 
X(a) 
X 
X 
X 
X 
X 
FFA, adiponectin, Leptin and apoA1 
 
 
 
X 
  
  
X 
  
Chemistry 
Plasma Iron, Transferrin, Ferritin 
M 
 
 
X 
  
  
X 
  
Fibrosis markers 
TIMP-1, TIMP-2, Cytokeratin K18, hyaluronic acid, 
P3NP, FGF 21 (non-exhaustive list) 
 
 
  
X 
  
  
X 
  
Exploratory criteria Biobank 
 
 
  
  
  
  
  
  
Other biomarkers 
IL-6, IL-13, IL-17A, IL1B, TNF-a, INFg, APO B, APO C3, 
MMP2, MMP9, ProC3  (non-exhaustive list) 
 
 
  
X 
  
  
X 
  
Genotype 
PNPLA3, TM6FS2  
 
 
  
X(d) 
  
  
  
  
Safety assessments 
 
 
  
  
  
  
  
  
Hematology 
WBC (+diff. Count), RBC, hemoglobin, MCV, hematocrit, 
Platelets, reticulocytes, CCMH, Hematocrit 
X  
 
X(a) 
X 
X 
X 
X 
X 
Inflammatory markers 
Nt-ProBNP 
 
 
 
X 
  
  
X 
 
Chemistry 
creatinine, urea, albumin, CPK 
X  
 
X(a) 
X 
X 
X 
X 
X 
Liver tests  
AST, ALT, ALP, GGT, total bilirubin 
X  
 
X(a) 
X 
X 
X 
X 
X 
Bone 
B-Crosslaps, Osteocalcin 
 
 
 
X 
  
  
X 
 
Coagulation factors 
INR 
X  
 
X(a) 
X 
X 
X 
X 
X 
Urine dipstick 
Hematuria 
 
 
 
X 
 
X 
X  
X 
Pharmacokinetics: lanifibranor (+ metabolites) trough sampling 
 
 
 
 
X 
 
X 
 
Adverse events 
 
 
 
X 
X 
X 
X 
X 
Dispense study treatment 
 
 
 
X 
X 
X 
 
 
Compliance check 
 
 
 
 
X 
X 
X 
 
(a) to be done only if there are more than 4 weeks between V-1 and V0; 
(b) to be done after checking inclusion / exclusion criteria, incl. lab tests , ECG  and Fibroscan; 
(c) to be done after checking the results of the Fibroscan and/or the Liver MultiScan/ Magnetic Resonance (in selected centers); 
(d) Only for patients having consent for genetic testing; 


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Table of contents 
SIGNATURE PAGE (SIGNATURES ON FILE) .......................................................................2 
REVISION HISTORY ..................................................................................................................3 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS ............................................................................................................14 
LIST OF FIGURES .....................................................................................................................17 
LIST OF TABLES .......................................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
1. 
INTRODUCTION ................................................................................................................22 
1.1 
Non Alcoholic Steato-Hepatitis (NASH) ...............................................................22 
1.2 
Peroxisome Proliferator-Activated Receptor (PPAR) in NASH ............................22 
1.3 
Investigational product ...........................................................................................24 
1.4 
Summary of lanifibranor Preclinical and clinical data ...........................................25 
1.5 
Rationale of the Study Design ................................................................................29 
2. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................33 
2.1 
Investigators and Other Participants ......................................................................33 
2.2 
Sponsors Representatives .......................................................................................33 
2.3 
Pharmacovigilance and safety Institution ..............................................................33 
2.4 
Other relevant Institutions ......................................................................................33 
3. 
ETHICAL AND LEGAL CONSIDERATIONS ................................................................34 
3.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) .............34 
3.2 
Protocol Amendments ............................................................................................34 
3.3 
Ethical Conduct of the Study .................................................................................35 
3.4 
Good Clinical Pratice Responsibilities ...................................................................35 
3.5 
Reporting of safety issues breaches of the protocol or ICH GCP ..........................35 
3.6 
Insurance ................................................................................................................36 
3.7 
Patient Information and Consent ............................................................................36 
3.8 
Premature Termination ...........................................................................................36 
3.9 
Definition of end of the trial: ..................................................................................36 
4. 
STUDY OBJECTIVES AND INVESTIGATIONAL PLAN ............................................37 
4.1 
Study Design ..........................................................................................................37 
4.2 
Study Population ....................................................................................................38 
4.3 
Study Medication ...................................................................................................42 


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5. 
MEASUREMENTS ASSESSED AND STUDY FLOW CHART ....................................45 
5.1 
Table of study procedures and assessments ...........................................................45 
5.2 
Specific procedures for Assessment of outcomes ..................................................45 
5.3 
Procedures at each visit ..........................................................................................48 
6. 
SAFETY ASSESSMENT .....................................................................................................51 
6.1 
Adverse Events .......................................................................................................51 
6.2 
Serious Adverse Events or Reactions .....................................................................53 
6.3 
Safety Variables .....................................................................................................54 
6.4 
Data Safety Monitoring Committee .......................................................................58 
7. 
PHARMACOKINETIC ASSESSMENTS .........................................................................59 
7.1 
IMP Concentration Measurements .........................................................................59 
7.2 
Non-Compartimental Pharmacokinetic analysis ....................................................60 
8. 
DATA QUALITY ASSURANCE ........................................................................................60 
8.1 
Monitoring ..............................................................................................................60 
8.2 
Data recording ........................................................................................................61 
8.3 
Data management ...................................................................................................61 
8.4 
Independent Audit ..................................................................................................62 
8.5 
Regulatory Inspection ............................................................................................62 
9. 
STATISTICAL METHODS ................................................................................................62 
9.1 
Efficacy Assessments .............................................................................................62 
9.2 
Sample Size ............................................................................................................63 
9.3 
Randomization .......................................................................................................64 
9.4 
Protocol Deviations ................................................................................................64 
9.5 
Data sets Analyzed .................................................................................................64 
9.6 
Demographic and Other Baseline Characteristics ..................................................65 
9.7 
Safety Analysis .......................................................................................................65 
10. PATIENT WITHDRAWAL & REPLACEMENT ............................................................69 
10.1 
Patient Withdrawal .................................................................................................69 
10.2 
Unblinding Process ................................................................................................70 
11. TRAINING & INFORMATION .........................................................................................71 
11.1 
Training ..................................................................................................................71 
11.2 
Information of the Investigator ..............................................................................71 
12. RECORDS & DATA ............................................................................................................71 
12.1 
Source Records & Data ..........................................................................................71 


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12.2 
Case Report Forms .................................................................................................72 
13. CONFIDENTIALITY ..........................................................................................................72 
13.1 
Confidentiality of Patient Data ...............................................................................72 
13.2 
Confidentiality of sponsor Data .............................................................................72 
14. REPORTING & PUBLICATION .......................................................................................72 
14.1 
Study Report ...........................................................................................................72 
14.2 
Disclosure of Data and Publications ......................................................................73 
15. RECORD KEEPING ............................................................................................................73 
15.1 
Study Site Records .................................................................................................73 
15.2 
Study Master File ...................................................................................................73 
BIBLIOGRAPHY ........................................................................................................................74 
APPENDICES ..............................................................................................................................80 
 
 


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List of Figures 
FIGURE 1: NATIVE STUDY DESIGN AND SCREENING PROCESS .................................................11 
FIGURE 2: LANIFIBRANOR REDUCES INFLAMMATION AND STEATOSIS IN A 3 WEEKS MCD MODEL
........................................................................................................................................................26 
FIGURE 3: PHASE IIA BIOMARKERS OF LANIFIBRANOR PPAR ACTIVATION IN DIABETIC PATIENTS
........................................................................................................................................................31 
FIGURE 4: IMP PACKAGING .......................................................................................................43 
FIGURE 5: HISTOLOGICAL GRADING USED IN SAF SCORE. GRADING OF STEATOSIS. ..................92 
List of Tables 
TABLE 1: STUDY SCHEDULE OF PROCEDURES (IF A LIVER BIOPSY OF LESS THAN 6 MONTHS IS 
AVAILABLE BEFORE SCREENING) .....................................................................................................12 
TABLE 2: STUDY SCHEDULE OF PROCEDURES (IF A LIVER BIOPSY IS NOT AVAILABLE BEFORE 
SCREENING) ....................................................................................................................................13 
TABLE 3: INTERSPECIES COMPARISON OF HUMAN AND ANIMAL PLASMA EXPOSURE TO 
LANIFIBRANOR IN GENERAL TOXICITY STUDIES .............................................................................28 
TABLE 4 : INTERSPECIES COMPARISON OF HUMAN AND ANIMAL PLASMA EXPOSURE TO 
LANIFIBRANOR IN SEGMENT II REPRODUCTIVE TOXICITY STUDIES ................................................28 
TABLE 5: SUMMARY OF LABELLING DETAILS ............................................................................44 
TABLE 6 : BLOOD VOLUME TAKEN AT EACH VISIT PER TYPE .......................................................46 
TABLE 7 : CENTRAL LABORATORY TESTS FOR SAFETY ASSESSMENT ..........................................55 
TABLE 8 : CENTRAL LABORATORY TESTS FOR EFFICACY ASSESSMENT ......................................56 
TABLE 9 : BIOBANK TESTS..........................................................................................................57 


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List of Abbreviations and Definitions of terms 
ADR 
Adverse drug reaction 
AE  
Adverse event 
AHA 
American Heart Association 
ALP 
Alkaline phosphatase 
ALT  
Alanine amino transferase 
AST 
Aspartate amino transferase 
AUC 
Area Under the Curve 
AUC[0→24h] 
Area under the plasma concentration curve from administration to 24h 
AUC[0→t]  
 Area under the plasma concentration curve from administration to last observed 
concentration at time t 
AUC[0→∞]  
 Area under the plasma concentration curve from administration to infinite time 
bpm beat per minute 
BCS 
Biopharmaceutics Classification System 
BMI 
Body mass index 
CA 
Competent Authority 
CAP 
Controlled Attenuation Parameter 
CEC 
Competent Ethics Committee 
CBC 
Complete blood count 
CCL4 
Chemokine (C-C motif) ligand 4  
CDaa 
Choline deficient l-amino acid 
CL 
Central Laboratory 
Cmax 
Maximal plasma concentration 
CPK 
Creatine phosphokinase 
CRF 
Case Report Forms 
CRN 
Clinical Research Network 
CRP 
C reactive protein 
CV 
Coefficient of variation 
D 
Day 
DBP 
Diastolic Blood Pressure 
DNA 
Deoxyribonucleic acid 
DcSSc 
Diffuse cutaneous systemic sclerosis 
ECG 
Electrocardiogram 
ECM 
Extra-Cellular Matrix 
eCRF 
Electronical Case Report Forms 


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eGFR 
estimated glomerular filtration rate 
EGF 
Epidermal Growth Factor 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FFS 
Flinders Fatigue Scale 
γGT 
Gamma glutamyl transpeptidase 
GCP 
Good Clinical Practice 
h 
hour(s) 
HBV 
B virus hepatitis  
HCV 
C virus hepatitis  
HDL-C 
High-density lipoprotein cholesterol 
HDPE  
High-density polyethylene 
HFD 
High-fat diet 
HOMA 
Homeostasis model assessment of insulin resistance  
HR 
 Heart rate 
HSC 
Hepatic stellate cells  
hs-CRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for human Use 
IEC 
Independant ethics committee 
IFN 
Interferon 
IL 
Interleukin 
IMP 
Investigational medicinal product  
in 
inch 
INR 
International normalized ratio 
ITT 
Intention to Treat 
IWRS 
Interactive Web Response System  
KO mice 
Knock-out mice 
lbs 
pound 
LDL-C 
Low density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LIF 
Liver Inflammation and Fibrosis  
LMS 
LiverMultiScan 
MCD 
Methionine Choline deficient 
MCHC 
Mean corpuscular haemoglobin concentration 


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MCP 
Monocyte Chemoattractant Protein 
MCV 
Mean corpuscular volume  
MedDRA 
Medical Dictionnary for Regulatory Affairs 
MHC 
Mean hemoglobin concentration 
MTD 
Maximum tolerated dose  
MRI 
Magnetic resonance imaging 
MRI-PDFF 
MRI proton density fat fraction 
NAFLD 
Non-alcoholic fatty liver disease  
NAS 
NAFLD Activity Score  
NASH  
Nonalcoholic steatohepatitis 
NNT 
Number Needed to Treat 
NOAELs 
No observed adverse effects levels 
P3NP 
N-terminal Pro-peptide of type III Procollagen 
PBO 
Placebo 
PCR 
Polymerase chain reaction 
PDGF 
Platelet-Derived Growth Factor 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PPAR 
Peroxisome Proliferator-Activated Receptor 
PQ 
PQ interval: duration in milliseconds from the beginning of P wave to onset of 
ventricular depolarization (Q and R) 
Pro-C3 
N-terminal Pro-peptide of type III Collagen 
PTM 
Placebo to match  
PTT 
Partial Thromboplastin Time 
QD 
Once a day (Quaque Die (Latin: Daily)) 
QRS 
QRS interval: duration in milliseconds of the QRS-complex 
QT 
QT interval: duration in milliseconds from the beginning of 
 
Q wave to the end of T wave 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAF 
Steatosis Activity Fibrosis 
SAP 
Statistical Analysis Plan  
SBP 
Systolic blood pressure  


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SD 
Standard deviation 
SF36 
Short Form (36) Health Survey 
SMA 
α-Smooth Muscle Actin 
SO 
Safety officer 
TBARS 
Thiobarbituric Acid Reactive Substances 
TE 
Transient Elastography  
TC 
Total cholesterol 
t1/2 
plasma concentration half life 
tlag 
Time delay between drug administration and the onset of drug absorption 
T2DM 
Type 2 Diabetes Mellitus 
TE 
Transient Elastography 
TEAE 
Treatment-emergent adverse event 
TG  
Triglycerides  
TGF 
Transforming growth factorTmax Time passed since administration at which 
the maximum plasma concentration occurs 
TNF 
Tumor Necrosis Factor 
TSC 
Trial Steering Committee 
UUO 
Unilateral Ureteral obstruction 
ULN 
upper limit of the normal range 
V 
Visit 
VEGF 
Vascular Epidermal Growth Factor 
WBC 
White blood cell 
WMA  
World Medical Association 
WT mice 
Wild type mice 


 
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1. Introduction 
This is a phase IIb, randomized, double-blind, placebo-controlled, multicenter, dose-range, 24-
week treatment study of IVA337 (lanifibranor) in adult subjects with nonalcoholic steatohepatitis 
(NASH). 
This introductory section describes briefly the underlying conditions of the patients to be 
included in the study, the scientific rationale for exploring lanifibranor in NASH, summarizes the 
lanifibranor preclinical and clinical data and provides a rationale for the study design. 
1.1 
Non Alcoholic Steato-Hepatitis (NASH) 
Non-alcoholic steatohepatitis is a liver disease characterized by fatty infiltration of the liver 
together with signs of inflammation and hepatocyte injury. Although pathophysiology is complex, 
its primary cause is still believed to be insulin resistance, as NASH occurs mostly in individuals 
that are overweight/obese or have type 2 diabetes (1). Because of the significant increase in the 
incidence of obesity and diabetes, NASH is rapidly becoming one of the major and most prevalent 
causes of liver diseases, ranking in the top 3 hepatopathies in different countries and ethnic 
backgrounds. This trend is expected to increase in the years to come. 
The prognosis of NASH is determined both by progression of hepatic disease and by 
extrahepatic complications (2). Hepatic fibrosis progression is the main hepatic complication of 
NASH (3,4) and can culminate in the occurrence of cirrhosis with its major risks and complications 
(5,6). Extrahepatic complications include an increased risk of cardiovascular events and 
cardiovascular morbidity that seems to be independent of other known cardiometabolic risk factors 
(7–9). Several studies have now shown that patients with NASH have reduced survival compared 
to the age and sex-matched general population (10) and that they are exposed to the risk of end-
stage liver disease (5,9), hepatocellular carcinoma (5,11) and increased liver-related mortality (9). 
Treatment of NASH is a significant unmet clinical need. While diet and lifestyle changes are 
always to be recommended as first-line therapy and can be efficient in reducing NASH histological 
lesions, most patients fail to reach these objectives and compliance with these measures is usually 
poor (12,13). Therefore, targeted pharmacological therapies are usually necessary. It is now 
recognized that insulin resistance is the main mechanism leading to fat accumulation in the liver 
and insulin-sensitizing agents such as glitazones (14) and metformin (15) have been proposed as 
putative treatments of NASH. However, although some studies suggest a moderate efficacy of 
glitazones (the early-phase studies have shown that at least half of treated patients have no or a 
suboptimal response to glitazones (16) definitive proof of their efficacy is lacking and regarding a 
meta-analysis demonstrated no benefit (17)(18). 
It is now recognized that development and progression of NASH is the result of a multi-step 
process (19). Insulin resistance promotes the transition from normal to fatty liver (20) while 
numerous additional factors ("hits") trigger the development of steatohepatitis in patients with 
steatosis. 
1.2 
Peroxisome Proliferator-Activated Receptor (PPAR) in NASH 
 Rationale for PPAR in NASH 
The PPARs are ligand-activated transcription factors belonging to the nuclear hormone receptor 
family. A wide range of ligands can bind to the PPAR receptors resulting in a broad range of 
cellular signaling and biological processes. They are involved in development, reproduction, 


 
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inflammation, immune function, metabolism, apoptosis, growth and cancer (21,22). There are 3 
PPARs isotypes, PPARα, PPARβ/δ and PPARγ. PPARα is highly expressed in the liver, especially 
in hepatocytes, and is implicated in the fatty acid transport, β-oxydation and the inflammatory 
response (23,24). The fibrates are synthetics ligands of PPARα and are used to treat dyslipidemia. 
PPARβ/δ is known to be involved in hepatic glucose utilization, lipoprotein metabolism, 
proliferation and to also have an anti-inflammatory activity within the liver (25–27). PPARγ is 
essentially expressed in the adipose tissue where it regulates inflammation, increases insulin 
sensitivity and promotes fatty acid uptake (28). Glitazones are the most described chemical family 
of PPARγ synthetic ligands. They have been developed for their antidiabetic and insulin sensitizing 
effect. 
The synthetic ligands of PPARs, fibrates and glitazones were hence developed and tested for 
the treatment of dyslipidemia, to improve glucose homeostasis and for type 2 diabetes mellitus. 
NASH is considered as the hepatic manifestation of the metabolic syndrome, which is a set of 
events that could lead to diabetes, cardiovascular disease, and cerebrovascular accident (29). 
PPARs are known to be involved in several aspects of Non-alcoholic fatty liver disease (NAFLD) 
such as the hepatic triglyceride accumulation, which is the hallmark of this disease. Moreover, data 
suggest that PPARs are involved in the process of fibrogenesis (30). In hepatic fibrosis, PPARs, 
and especially PPARγ, have a role in preventing the activation of hepatic stellate cells, the key 
cells of the hepatic fibrotic process (30,31). 
In patients, pioglitazone, a PPARγ agonist, at the dose of 30 mg/day for 96 weeks, significantly 
reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as hepatic 
steatosis and lobular inflammation compared to placebo (32). In another study, at the dose of 
45 mg/day for 24 weeks and in association with a 500 Kcal reduction diet, pioglitazone 
significantly decreased ALT and AST and was associated with a significant improvement of 
steatosis, ballooning necrosis and inflammation (14). Furthermore, PPARα expression negatively 
correlates with the severity of NASH (33). 
Taken together the beneficial effects of PPARs in NAFLD, inflammation and in fibrosis suggest 
them as a promising candidate for the treatment of NASH 
 PPARs in preclinical NASH model 
There is currently no experimental model replicating all the different aspect of human NASH. 
However, several models exist that reproduce part of, or even most of, the human pathology 
features. Among these models, the most frequently used is the Methionine Choline deficient 
(MCD) diet. The effects of several PPARs agonists have been tested in this model. 
It had been demonstrated that PPARα knock-out mice (KO Mice) are more sensitive to develop 
steatohepatitis under MCD diet than wild type mice (WT mice) (34). In the same way, treatment 
with Wy-14643, a PPARα agonist, in a prophylactic or curative mode could prevent or reverse 
MCD-induced steatohepatitis (34,35). Moreover Wy-14643 could also reduce the hepatic fibrosis 
induced by MCD diet (35). In a model of APOE2 KO mice (fed with western high fat diet leading 
to steatosis and inflammation), the administration of fenofibrate prevents steatosis and expression 
of inflammatory markers (36). 
A positive effect of PPARβ/δ has been demonstrated in the MCD diet in mice where GW501516 
prevents steatosis inflammation (illustrated by a decrease in Ribonucleic acid (RNA) expression 
of TGF-β1, IL-6, IL-1β, MCP-1, TNF-α) and Hepatic Stellate Cells (HSC) activation (37). 
Moreover an exacerbated phenotype of Chemokine (C-C motif) ligand 4 (CCL4–induced) 


 
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hepatotoxicity was observed in PPARβ/δ null mice including increase in serum ALT and increase 
in mRNA related to fibrosis such as α-Smooth Muscle Actin (α-SMA) (38). 
The beneficial effect of PPARγ in NASH was demonstrated in the MCD diet model by 
overexpressing PPARγ by the administration of adenovirus carrying PPARγ. Mice overexpressing 
PPARγ demonstrated a prevention of steatosis, inflammation and fibrosis (39–41). The effect was 
stronger with the addition of rosiglitazone, a selective PPARγ agonist. On the contrary, mice 
deficient for PPARγ and treated with rosiglitazone or mice overexpressing PPARγ and treated with 
GW9662 (a PPARγ antagonist) presented a more severe steatohepatitis (39,40). Similarly to these 
studies, the administration of rosiglitazone prevented steatohepatitis and fibrosis in a model of 
middle-aged male low-density lipoprotein receptor (LDLR)(-/-) mice fed a high-fat diet 
(HFD)(42). The beneficial effect of PPARγ was also studied using pioglitazone, another PPARγ 
agonist. Pioglitazone demonstrated beneficial effects on steatohepatitis and a slight effect on 
fibrosis in a choline deficient L-amino acid defined diet (CDAA) rat model of NASH (43). In a 
model of HFD mice or rat and in a model of MCD mice, pioglitazone demonstrated beneficial 
effects on steatosis (44–46) as well as on insulin resistance. Pioglitazone has also been tested in a 
CCL4-induced liver fibrosis model where its effect is limited because it is dependent on the 
duration and severity of the disease (43). However, it is of importance to notice that it has been 
demonstrated by several publications that PPARγ plays a role in the fate of HSC cells. Indeed, a 
decreased expression of PPARγ in HSC is observed during the transdifferentiation from a 
quiescent state to an activated and proliferative state(47–50). PPAR, PPAR ligands (like the dual 
PPAR GFT505 and KD3010) and PPAR, all protect to various extent, from CCL4-induced, 
MCD diet-induced and bile duct ligation-induced fibrosis (51,52). 
1.3 
Investigational product  
IVA337, lanifibranor, a new chemical entity, (4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-
1H-indol-2-yl]butanoic acid) is an almost white to light brown colored solid. 
Structural formula, including relative and absolute stereochemistry: 
Molecular Formula: 
C19H15Cl N2O4S2 
Molecular weight: 
434.92 
Chirality: 
No asymmetric carbon 
Polymorphism: 
β form crystal 
The Investigational Medicinal Product is a white to off-white bi-convex tablet, weighing 
approximately 927 mg and showing a breakline to facilitate the administration to patients. The 
film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate 
release formulation. 
Film-coated tablets with a core containing 900 mg of a physical mixture of lactose 
monohydrate, microcrystalline cellulose, pre-gelatinised starch and magnesium stearate serve as 
placebo. 
The Investigational Medicinal Products used in this clinical phase IIb trial will be packaged in 
containers of High Density Polyethylene (HDPE) with proper HDPE closures fitted with a silica 
cartridge. 
Based on the results of the ongoing stability studies, a shelf life of 2 years (storage at 25°C or 
below) is proposed for the Investigational Medicinal Product provided it is stored in the original 
package, the HDPE bottles.  


 
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Furthermore, the stability data at 40°C/75%RH demonstrate that temperature excursions (e.g. 
during shipment, storage) will not significantly affect the stability of lanifibranor 400 mg film-
coated tablets.  
To avoid the potential moisture ingress, which may happen during the use of the monthly pack, 
a twist-off cap integrated with a 2 g of silica gel has been selected for the closure. The data of the 
“in use test” 35 days at 25°C/60%RH open bottles have confirmed the stability of the 
Investigational Medicinal Product during its proposed clinical use. 
1.4 
Summary of lanifibranor Preclinical and clinical data 
 Pharmacology 
NASH is a multifactorial and multi-step disease. A first component of this pathology includes 
the metabolic syndrome related to insulin resistance, triglyceride accumulation, obesity etc. A 
second component is the fibrosis. In our pre-clinical studies, we demonstrated the beneficial effect 
of lanifibranor in several component of the metabolic syndrome as well as in fibrosis. 
Lanifibranor, in previous experiments, was shown to exert an anti-diabetic and 
antihyperlipidemic activity in db/db mice, ZDF rats, diet-induced obese mice and the WOKW rat 
model of metabolic syndrome. Furthermore, it increased serum apoA1 level in human apoA1 
transgenic mice. In functional cellular tests, lanifibranor increased fatty acid β-oxidation, 
stimulated cholesterol efflux, induced the expression of aP2 and adiponectin genes as well as 
ABCA1, ABCG1 and LXRα genes, while it reduced MCP-1 secretion. All these effects are 
signature of the activation of the 3 PPAR receptor isoforms. 
Recently, it was demonstrated in vivo that lanifibranor displays an antifibrotic activity in 
bleomycin-induced lung fibrosis, in bleomycin-induced skin fibrosis (in preventive and curative 
mode), in a model of unilateral ureteral obstruction (UUO)-induced kidney fibrosis and in CCL4-
induced fibrosis in the liver. In the liver, lanifibranor is active in both preventive as well as curative 
mode, thus providing evidence for an anti-fibrotic effect in established fibrotic disease. In the liver 
it was demonstrated that lanifibranor at 15 and 30 mg/kg was able to inhibit in a dose dependent 
manner the collagen deposition within the liver (-42% and -73.16% respectively). Lanifibranor 
was also able to decrease the serum triglycerides and ALT.  
HSC are the cells responsible for the secretion the Extra-Cellular Matrix (ECM) and especially 
the collagen when activated (myofibroblast transdifferenciation of HSC). The main cellular 
process underwent by the HSC in a fibrogenenic environment is proliferation and activation. The 
proliferation assay is based on PDGF and the activation is based on stiffness (stiffness of the plated 
plastic). PDGF is secreted by a variety of cell types and plays a central role in fibrogenesis. It 
induces HSC proliferation and migration, thus contributing to the increase of the number of matrix-
secreting cells. During fibrosis, the growing deposition of ECM increases the stiffness of the liver 
and participates to myofibroblast transdifferentiation of HSC. Lanifibranor was able to fully inhibit 
the proliferation induced by PDGF and was able to prevent the overexpression of α-SMA and the 
hallmark of myofibroblast, induced by stiffness. These findings strongly support the anti-fibrotic 
action of lanifibranor in the target cells. 
Activity of lanifibranor on liver steatosis and inflammation, two main components of NASH, was 
evaluated in a 3-week model of MCD diet in C57bl/6 mice (report in preparation). It was shown 
that lanifibranor prevented steatosis in a dose-dependent manner at the doses of 10 and 30 mg/kg 
(-88.38% and -97.89% respectively compared to vehicle, see Figure 2). Lanifibranor also 
prevented inflammation at the doses of 10 and 30 mg/kg (-44.03% and -74.49% respectively 


 
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compared to vehicle). Lanifibranor also prevented the increase in ALT transaminase induced by 
MCD diet (-49.35% and 67.26% at 10 and 30 mg/kg respectively), demonstrating hepatoprotective 
effect. 
Figure 2: Lanifibranor Reduces Inflammation and Steatosis in a 3 Weeks MCD Model 
 
 Pharmacokinetics 
Lanifibranor is considered as a class II compound as regard to the Biopharmaceutics 
Classification System (BCS) Guidance: high permeability and low solubility. It was evidenced in 
all tested species that lanifibranor absorption is dependent on the drug substance form and 
formulation, leading to a bioavailability in animals from 15% up to >80%. An enterohepatic 
recycling was evidenced, and a food effect was observed in human in the presence of high fat 
breakfast. 
After oral administration in human, maximum plasma levels (Cmax) of lanifibranor were 
reached at about 1.0-3.5 h, and terminal plasma elimination half-life was around 10-15 h. Both 
Area Under the Curve (AUC) and Cmax increased in a linear but slightly less than dose-
proportional manner. Steady-state lanifibranor concentrations were generally achieved by Day 3 
after daily dose administration, with no significant accumulation. 
The mean apparent volume of distribution Vz/F ranged from 318 to 607 L in healthy subjects. 
Lanifibranor was extensively distributed in monkeys (~10 L/kg). IVA337 binds very highly to 
plasma proteins in all tested species (~99.9%) and no affinity to blood cells was observed. By 
autoradiography in rat, lanifibranor was shown to be mainly distributed in the excretory organs 
(liver, kidneys, lungs, gastrointestinal tract) and in placenta in pregnant rats with no affinity for the 
melanin tissues and with very limited central nervous system penetration. 
Lanifibranor-related radioactivity elimination was mainly faecal (>85%) and the urinary 
excretion was minor (<7%) with a very low renal clearance. The excretion was essentially 
complete after 3 days. 
AUC indicated approximately 23% of the radioactivity in plasma were related to lanifibranor, 
while 77% were related to its metabolites. Lanifibranor was observed in vitro to be metabolized 
either by enzymes of phase I (mainly via CYP isoforms CYP2C8, 2C19 and 3A4) and phase II 
(mainly via UGT 2B7, 1A1 and 1A3). No affinity of lanifibranor to uptake or efflux transporters 
as substrate was evidenced in vitro. 
Among metabolites identified in plasma, faeces and urine, the main lanifibranor metabolites 
observed in human were the acyl glucuronide (IV1197736, with similar exposure to that of the 
parent compound), a monohydroxylated (IV1537661) and the benzothiazole ring opened 
lanifibranor derivative (IV1197347). All other metabolites were reported to represent less than 5% 


 
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of the administered dose (14C-ADME study in human). The completion of the quantitative 
comparison of the animal versus human plasma exposure to these three metabolites is ongoing. 
Lanifibranor was shown to be an inhibitor of CYP2C8 (IC50 4µM, Ki 8µM), CYP2C9 (IC50 
8µM, Ki 21µM), CYP2C19 (IC50 25µM) and CYP2B6 (IC50 8µM). A limited risk of CYP 
induction could be expected in vivo, as only a slight CYP3A4 induction was observed at 20 µM of 
lanifibranor in one among all tested donors. No inhibition of xanthine and aldehyde oxydase 
inhibition by lanifibranor was evidenced. Lanifibranor directly inhibited UGT1A1, UGT1A3, 
UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15 and UGT2B17 with IC50 values of 13, 26 to 
38, 20, 83, 42, 33, 23 and 22 μM, respectively. Lanifibranor was shown to inhibit uptake and efflux 
transporters but with relatively high IC50 values: MDR1 (8.5 μM), BCRP (15.2 μM), BSEP 
(16.8 μM), OCT2 (267 μM), except for OATP1B1/3 (~1 µM). No significant drug-drug interaction 
was observed with Simvastatin (<2-fold), and no PK/genotype (CYP450 isoenzymes and UGTs 
isoform) relationship has been identified. There were a 22% increase in Cmax and 39% increase 
in AUC of lanifibranor in elderly subjects as compared to young subjects. 
 Toxicology 
Lanifibranor has a very low acute toxicity (maximal non-lethal dose of 2000 mg/kg in rodents) 
and is not irritating to the skin. 
Lanifibranor is devoid of genotoxic potential in the full international conference on 
harmonization (ICH) battery of genotoxicity assays. The three major human metabolites, 
IV1197736, IV1197347 and IV1537661, were also found devoid of genotoxic potential in a 
bacterial reverse mutation test and a mammalian cell assay. 
Lanifibranor is devoid of deleterious effects on vital functions such as cardiovascular, central 
and autonomic nervous system and respiratory system. In a 9-week head-to-head comparative 
study in rats aimed at evaluating side effects of PPAR agonists such as plasma volume expansion 
and secondary cardiac hypertrophy, or skeletal muscle toxicity, daily doses of lanifibranor up to 
1000 mg/kg compared favorably with other PPAR agonists rosiglitazone, muraglitazar and 
tesaglitazar. These observations were substantiated in repeated dose toxicity studies with 
lanifibranor in rats and monkeys. 
No potential risks have been identified from pivotal toxicology studies with lanifibranor in rat 
and in monkey and segment II reproductive toxicity studies in rats and rabbits. All treatment-
related findings (i.e. liver, bone marrow, adipose tissue) were reversible.  
 
 


 
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Table 3: Interspecies Comparison of Human and Animal Plasma Exposure to 
Lanifibranor in General Toxicity Studies 
Table 4 : Interspecies Comparison of Human and Animal Plasma Exposure to 
Lanifibranor in Segment II Reproductive Toxicity Studies 
Species/Strain 
NOAEL (mg/kg/d) 
Plasma Exposure 
(AUC0-24 as µg.h/mL) 
Gender 
lanifibranor 
Han Wistar Rat 
100 
Female 
437 (8.7)1 
New Zealand White 
Rabbit 
3 
Female 
105 (2.1) 
1 
values in brackets show exposure margin factor to clinical exposure 
The safety margins over expected human exposure in general toxicology studies were at least 
20-fold in rats and 2-fold in monkeys ( 
 
Human Plasma 
AUC at Estimated 
Active Dose 
(µg.h/mL) 
Species 
NOAEL 
Male-
Female 
(mg/kg/d) 
AUC at 
NOAEL 
Male-Female 
(µg.h/mL) 
Safety 
Margin 
50 
Mouse* 
25 
225 - 278 
~5 
Rat** 
2000 
- 
1000 
798 - 1144 
16 - 23 
Monkey## 
1000 
110 - 82 
1.6 - 2.2 
*: from 13-week toxicology study in CD-1 mice 
**: from 13-week toxicology study in Wistar rats 
##: from 26-week toxicology study in Cynomolgus monkeys 


 
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Table 3). The safety margins over expected human exposure established in segment II 
reproductive toxicity studies were 9-fold in rats and 2-fold in rabbits (Table 4). A preliminary 2-
week pharmacokinetic and toxicity study in the mouse, where plasma exposures were markedly 
higher than those achieved in volunteers given the highest tested dose of 1500 mg/day for two 
weeks (approximately 40-fold) and higher than those achieved in the chronic rat study, has 
evidenced signs of toxicity for the kidney, the heart and the skeletal muscles, in particular myositis 
of skeletal muscles, minimal to moderate myocarditis and tubulo-interstitial nephritis. These 
organs are known targets for toxicity of PPAR agonists. However, a recently conducted 13-week 
study in mice established an adequate 5-fold safety margin over expected human exposure at a 
NOAEL (no observed adverse effects levels) of 25 mg/kg/day. 
 Previous Lanifibranor Clinical Data 
Lanifibranor has previously been in clinical development up to Phase II for the treatment of 
type 2 diabetes. The development for diabetes was discontinued for strategic reasons. 
Three clinical studies have been conducted in healthy subjects, one study in patients with type 
2 diabetes, and one phase II study is ongoing in the treatment of diffuse cutaneous systemic 
sclerosis.  
The objectives of study S337.1.001 were to assess pharmacokinetics, pharmacodynamics, 
safety and tolerability of lanifibranor after single increasing doses and after multiple increasing 
doses.  
The objectives of study S337.1.002 were to study the effect of lanifibranor on the 
pharmacokinetics of simvastatin and simvastatin acid and to evaluate the pharmacokinetics of the 
two crystalline anhydrous solid alpha and beta forms of lanifibranor.  
The objectives of study S337.1.005 were to assess the relative bioavailability of lanifibranor 
oral suspension and capsules (cross-over design), and to assess, in vivo in human, the completeness 
of excretion, routes and rates of elimination of radioactivity, the metabolic pathways, and identity 
of lanifibranor metabolites after single administration of 14C-IVA337.  
The objectives of study S337.2.001 were to evaluate the safety, tolerability, pharmacokinetics 
and pharmacodynamics of lanifibranor in doses of 400 to 1200 mg daily over a 4-week period in 
patients with type 2 diabetes.  
The ongoing study IVA_01_337_HSSC_15_001 is a randomized, double-blind, placebo-
controlled, multicenter proof-of-concept trial of lanifibranor in the treatment of diffuse cutaneous 
systemic sclerosis (DcSSc). 
In clinical trials performed in healthy volunteers and patients with type 2 diabetes, lanifibranor 
was safe and well tolerated. Treatments included single doses of 25 mg to 1000 mg, multiple doses 
of 150 mg to 1500 mg once daily for 14 consecutive days, and once daily doses of 400, 800, and 
1400 mg for 4 weeks. The reported adverse events considered to have a causal relationship to the 
study drug included dizziness, postural dizziness, headache, hot flush, lethargy, somnolence, 
constipation, trends towards decreases in red blood cell count, haemoglobin and haematocrit in 
healthy volunteers, and hypochromic anaemia, constipation, urinary tract infection and headache 
in patients with type 2 diabetes. There were no clinically relevant time or dose-related changes on 
cardiac and muscle markers, liver enzymes or markers of renal function. The 12-lead 
electrocardiogram (ECG) did not show clinically significant changes. 


 
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1.5 
Rationale of the Study Design 
 General Considerations 
This study is a Phase IIb randomized (stratified on diabetes), double-blind, placebo-controlled, 
multicenter, dose-range, 24-week treatment study of lanifibranor in adult subjects with 
nonalcoholic steatohepatitis (NASH). 
 Rationale for the Choice of Dose and Duration of Repeated Administration 
The evaluated treatment will be as tablets of lanifibranor 400 mg, two doses of lanifibranor (800 
and 1200 mg once a day (QD)) versus placebo, i.e. three tablets (lanifibranor or indistinguishable 
placebo) per os, once daily, for 24 weeks. To improve bioavailability, drug intake is combined 
with food. 
Doses have been selected based on the available biomarker (adiponectin, HDL cholesterol, 
triglycerides) results in diabetes type 2 patients (Phase IIa study): 
 800 mg per day: lowest and statistically significant active dose on the markers of the three 
PPAR ,  and  activity 
 1200 mg per day: dosage showing consistent activity on the markers of PPAR ,  and  
activity, being well tolerated 
Pharmacodynamic biomarkers of PPARs activation in diabetic patients (Phase IIa study) are 
shown in Figure 3. 
Clinical, biological and ECG safety in healthy volunteers and diabetic patients has been shown 
to be good up to the top dose used in this trial or at doses that are higher. There is no toxicology 
target organ of major concern for the clinic.  
Placebo is chosen as the comparator, as there is no licensed treatment for NASH. 
Treatment duration has been set to 6 months. This is a phase IIb study and the aim to assess 
safety and efficacy in order to progress to a phase III. Improvement in ALT, AST, γGT as well as 
insulin resistance can be observed within a couple of months of treatment, as has been observed in 
several trials seen with other PPARs agonists (14,53), suggesting that treatment efficacy can be 
observed early in the course of treatment. Furthermore, histological changes, especially in 
necroinflammation, have been observed after a 6-month treatment with a PPARγ agonist (14). 
Therefore, taking into account the postulated end points, a treatment of 6 months in a proof of 
concept study is sufficient to assess study drug efficacy and will furthermore also limit the time on 
placebo for one third of the study patients. 
The study only imposes 6 visits including the screen and follow-up visits and, apart from the 
liver biopsy at screening if no historical biopsy is available within 6 months of the screening visit, 
and at the end of the treatment and periodic blood sampling, there are no other invasive procedures. 
There is a very limited number of prohibited medications that should not interfere with standard 
medical care of the patients. For obvious reasons, fibrates, as they are PPARα ligands, are not 
allowed, but dyslipidaemias can be treated with statins, which are allowed.  


 
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Figure 3: Phase IIa biomarkers of Lanifibranor PPAR activation in diabetic patients  
Two thirds of the patient are on verum treatment and can expect an improvement of their NASH 
and metabolic syndrome based on the results of previous clinical studies with PPARα, γ and α/δ 
agonists. The two doses chosen for the trial demonstrated significant improvement in biomarkers 
of PPAR α, γ and probably δ in diabetic patients. 
As there is still no non-invasive tool sufficiently validated to accurately assess both the 
diagnosis as well as the treatment response in NASH, the only reliable tool to assess treatment 
efficacy is liver histology. As the primary endpoint is related to the reduction of necroinflammatory 
changes, a liver biopsy is indispensable to assess treatment efficacy and is therefore requested at 
the end of treatment. This is in line with the most recent recommendations on clinical trials in 
NASH (54,55). This is also in line with the design of the large Phase III trials that are currently 
ongoing (www.clinicaltrials.gov) and in which multiple biopsies are required for treatment 
efficacy assessment in large numbers of patients. 
The study will require the usual specific informed consent form approved at each site to be 
signed by patients. The study does not impose any major change in the standard practice of liver 
biopsy at the site (see Appendix C). In a large (N=2084 biopsies performed for heterogeneous 
indications, mainly hepatitis C) nationwide French study published 15 years ago (56), no death 
was observed and the incidence of major complication was 0.57% (12 patients, vasovagal episode: 
4, hemoperitoneum: 1 patient with cirrhosis, biliary peritonitis: 3, pneumothorax: 1, puncture of 
other viscera: 3). These data have been confirmed with more recent publications, except that the 
introduction of ultra-sound guidance decreased dramatically the risk of perforation of other organs 
(57–61). The benefit/risk ratio of participation in the study is acceptable, i.e. out-patient procedure, 
in patients with controlled hemostatic parameters, no cirrhosis, etc. and other studies have been 
conducted with the same design. 
LS mean % change at D28 of HDL Cholesterol
Pl
Pl
LS mean % change at D28 of Triglycerides
Placebo                                  400 mg IVA337                              800 mg IVA337                         
1400 mg IVA337
Placebo                                              400 mg IVA337                                800 mg IVA337           
1400 mg   IVA337
Pl
LS mean % change at D28 of Adiponectin
Placebo                                  400 mg IVA337                             800 mg IVA337                         1400 mg IVA337


 
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The following section discusses the main histologic assessment criteria. 
 Justification for using the Steatosis Activity Fibrosis (SAF) histological score 
Although there has been some evolution in the diagnostic criteria defining NASH, there is 
currently a large consensus, endorsed by renowned hepatologists and liver pathologists, and widely 
accepted in the liver community (62) that the diagnosis of NASH requires the combination of all 
three of the following histological features: steatosis, ballooning/clarification of hepatocytes, and 
lobular inflammation (Appendix C). 
While steatosis is considered to be a relatively benign lesion, ballooning and inflammation 
define the so-called “activity” of NASH. Activity is very likely driving fibrogenesis, which is the 
main histological long term prognostic factor for liver-related and also non-liver-related mortality 
associated with NASH. Reducing activity to prevent fibrogenesis is the treatment goal evaluated 
in this clinical trial.  
At present, no non-invasive markers have been shown to be accurate enough to diagnose NASH 
or to assess treatment effect. More specifically, no non-invasive markers have been validated to 
assess the different components of the diagnosis of NASH or to assess the evolution of these 
different components upon treatment. Only for steatosis, a reliable non-invasive technique, namely 
MR spectroscopy, has been sufficiently validated. Steatosis is, however, only one component of 
the definition of NASH, and, as outlined before, the other aspects of the disease, especially activity 
and fibrosis, are pivotal in terms of prognosis and treatment efficacy. Liver biopsy, although an 
invasive procedure, hence remains the gold standard to establish NASH diagnosis and there is no 
surrogate marker available to assess the different features of NASH that constitute its definition or 
that allow to reliably assess treatment efficacy as it is defined in the present trial, as well as in other 
Phase II trials. Also in the current Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) approved Phase III trials, treatment efficacy is defined based on histological 
criteria and consequently liver biopsy is a prerequisite to accurately evaluate both the baseline liver 
status of the patient as well as the efficacy of the treatment after a predefined treatment period. 
The activity sub score of the SAF score has been chosen as the main assessment criteria (63).The 
SAF has been developed by the European FLIP Pathology Consortium (64).  
This scoring system assesses semi-quantitatively and separately Steatosis, Activity and Fibrosis 
as described in detail in the following section.  
The Activity score of SAF is the addition of hepatocyte ballooning, the hallmark of NASH, and 
inflammation (both assessed from 0 to 2). By giving an equal weight to both lesion and not 
including steatosis into this score, a grade of activity > 2 ensures to get at least 95% of NASH (63). 
Using Activity score A >3 ensures also that only the most severe NASH, which are those prone to 
develop fibrosis, will be selected.  
This selection of NASH cases with severe activity cannot be done as accurately by using the 
NAS score (the NAFLD Activity Score that is part of the NASH Clinical Research Network 
(NASH CRN) Scoring System) (65), a composite score that is the unweighted sum of the score of 
steatosis (from 0 to 3), ballooning (from 0 to 2) and inflammation (from 0 to 3). Since this score 
includes steatosis, which is supposed to be a benign lesion, and underweight ballooning (graded 
from 0 to 2) compared to steatosis and inflammation (each being graded from 0 to 3), this score 
does not reflect activity of the disease as accurately as does the activity score of SAF.  
Finally, the criteria chosen for the definition of ballooning in the SAF score have been shown 
to be highly reproducible, which guarantees also the robustness of these histological criteria (64). 


 
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2. Investigators and Study Administrative Structure 
2.1 
Investigators and Other Participants 
The study will be performed in at least 60 sites across Europe, United States of America (USA) 
and other countries worldwide (incl. Canada, Australia and Republic of Mauritius). 
Principal Investigators: Pr. Sven Francque, MD, PhD, Division of Gastroenterology and 
Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium; Pr. 
Manal F. Abdelmalek, MD, MPH, Division of Gastroenterology / Hepatology, Duke 
University, 40 Duke Medicine Circle, Clinic 2H / 2J, Durham, NC 27710, USA. 
2.2 
Sponsors Representatives 
Sponsor:  
Inventiva S.A, 
 
50 rue de DIJON, 21121 Daix, France 
 
Tel: +33 (0) 380 447 631 
 
Fax: +33 (0) 380 447 561 
Chief Medical Officer (CMO):  
Marie-Paule RICHARD, MD 
 
Tel: +33 (0) 698 697 594 
 
Email: marie-paule.richard@inventivapharma.com 
Person authorized to sign protocol on behalf of the Sponsor: Marie-Paule Richard 
Clinical Research Physician:  
Martine BAUDIN, MD 
 
Tel: +33 (0) 760 795 852 
 
Email: martine.baudin@inventivapharma.com 
The conduct of the study is delegated to the monitoring institution KEYRUS BIOPHARMA 
except for Bulgaria, where the conduct of the study is delegated to IQVIA, for Republic of 
Mauritius and La Réunion island, where the conduct of the study is delegated to SIMBEC-ORION, 
for USA, where the conduct of the study is delegated to COVANCE and for Slovenia and 2 sites 
in Poland, where the conduct of the study is delegated to CLINMARK. 
The overall implementation and follow-up of computerised systems (IWRS, eCRF), the Data-
management and the statistical analysis are delegated to KEYRUS BIOPHARMA. 
2.3 
Pharmacovigilance and safety Institution 
The Safety of the study is delegated to the pharmacovigilance provider solutions: 
 
STRAGEN SERVICES S.A.S., 
 
52 rue de la République, 69002 Lyon, France  
 
Tel: +33 (0) 4 78 42 95 26, fax: +33 (0) 4 78 42 55 71, 
 
Email: pharmacovigilance@stragen.com 
2.4 
Other relevant Institutions  
Central laboratory, Clinical biology and biomarker assays: 
BARC Global Central Laboratory, Industriepark 3B Zwijnaarde, 9052 Ghent Belgium 
Tel: +32 9 329 23 29 
NORDIC BIOSCIENCES (Additional Biomarker assay) Herlev Hovedgade 205-207, DK-2730 
Herlev, Denmark  


 
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Product Manufacturing: 
DELPHARM, 10 rue charbonneaux, 51100 Reims France 
Tel: +33 (0) 3 80 48 30 30 
Clinical Packaging: 
Amatsi group, 17 Rue des Vautes, 34980 Saint-Gély-du-Fesc, France 
Tel: +33 (0) 4 99 58 38 60 
Pharmacokinetics Assay Laboratory: 
ATLANBIO, Z.I. de Brais - 1 rue Graham Bell, 44600 Saint Nazaire, France 
Tél.: + 33 (0)2 51 10 01 00 
PhinC Development, Genopole Campus 1, Immeuble Génavenir 8, 5, rue Henri Desbruères,  
91 000 Evry, France 
Tel: +33 (0) 1 60 87 14 79 
Cardiac Safety, ECG Central Read:  
BANOOK Group: Villa Alsacienne 78, avenue du 20ème Corps 54000 Nancy, France. 
Histology and Central Liver Biopsy Reading: 
Liverpat – Pierre Bedossa, 28 rue de l’Amiral Hamelin, 75016 Paris, France 
3. Ethical and Legal Considerations 
It is the responsibility of Inventiva to have the prospective approval of the study from the 
Competant authority (CA) and the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). The IRB/EC and CA receive annual safety and interim reports and are informed 
about study stop/end in agreement with local requirements. 
3.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
The Sponsor must submit this protocol to the appropriate IRB/IEC, and is required to forward 
to the Investigator a copy of the written and dated approval/favorable signed opinion. 
The study (study number, Protocol title and version number), the documents reviewed 
(protocol, Informed Consent Form, Investigator’s brochure, etc.) and the date of the review should 
be clearly stated on the written IRB/IEC approval/favorable opinion. All correspondence with the 
IRB/IEC should be retained in the Investigator File. 
Investigational Product will not be released at the study site and the trial will not start until a 
copy of written and dated approval favorable opinion has been received by the Sponsor. 
3.2 
Protocol Amendments 
Any change to this protocol by the Investigator or the Sponsor must be discussed and agreed. 
The change, presented as an amendment in written form to the protocol, will be signed by the 
different parties (Investigator, Sponsor) and submitted to the IRB/IEC and whenever applicable to 
the CA for their approval. 
Following approval, the amendment will be sent to all participating Investigators. The 
amendment cannot be acted upon prior to the outcome of this decision. 


 
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Amendment regarding minor modifications (administrative modifications) will be submitted to 
the IRB/IEC for information purposes only and whenever applicable to CA. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC and CA 
approval is where the change is necessary to eliminate apparent immediate hazards to the patients. 
In that event, the Investigator must notify the IRB/IEC and Inventiva in writing immediately after 
the implementation. All updates to the Investigator’s Brochure, Protocol or any amedement-
impacted documents will be sent to the IRB/IEC and CA whenever applicable. 
If requested, a progress report could be sent to the IRB/IEC annually and a summary of the 
trial’s outcome could also be provided at the end of the clinical trial. 
3.3 
Ethical Conduct of the Study 
This protocol complies with the principles laid down by the 59th World Medical Assembly 
(Fortaleza 2013, Appendix A: World medical association declaration of Helsinki) and all 
applicable amendments laid down by the World Medical Assemblies, the guidelines of Good 
Clinical Practice CPMP/ICH/135/95, the European and applicable regulations per country, and any 
other relevant local requirement and laws.  
3.4 
Good Clinical Pratice Responsibilities 
The responsibilities of the Sponsor and the Investigator will be as defined in the ICH GCP 
guidelines and applicable regulatory requirements. The Investigator is responsible for adhering to 
the responsibilities of Investigators, for dispensing the IMP in accordance with the final protocol 
or an approved amendment, and for its secure storage and safe handling throughout the study. 
3.5 
Reporting of safety issues breaches of the protocol or ICH GCP 
In the event of any prohibition or restriction imposed by an applicable CA, or if the Investigator 
is aware of any information which might influence the evaluation of the benefits and risks of the 
IMP, Inventiva should be informed immediately!  
In addition, the Investigator will inform Inventiva immediately of any urgence safety measures 
taken by the Investigator to protect the study patients against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.  
According to Regulation 29A of the Medicines for Human Use Regulations 2004, as amended 
by Statutory Instrument 2006/1928 - Guidance for the Notification of Serious Breaches of GCP or 
the Trial Protocol: 
A serious breach is a breach which is likely to effect to a significant degree: 
- The safety or physical integrity of the subjects of the trial or 
- The scientific value of the trial. 
The Sponsor or a person legally authorised by the Sponsor shall notify the licencing authority 
in writing of any serious breach: 
- The conditions and principles of GCP in connection with that trial or 
- The protocol relating to that trial within 7 days of becoming aware of that breach. 
 


 
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3.6 
Insurance 
In case of a damage or injury occurring to a patient in association with the IMP or the 
participation in the study, the Sponsor has subscribed to an insurance policy covering, in its terms 
and provisions, its legal liability for injuries caused to participating persons and arising out of this 
research performed strictly in accordance with the scientific protocol as well as with applicable 
law and professional standards.  
The Sponsor is insured under a liability insurance program subscribed by the Sponsor to cover 
its liability as a Sponsor of clinical studies on a worldwide basis. All relevant insurance 
documentation is included in the file submitted to authorities approval of which is required. Each 
participating Investigator receives the statement on insurance policy applicable in his/her country 
for filing in the Investigator’s Study File.  
A copy of the certificate is filed in each Investigator site file and the Trial Master File. 
3.7 
Patient Information and Consent 
The Investigator (according to applicable regulatory requirements), or a person delegated by 
the Investigator, should fully inform the patient of all pertinent aspects of the clinical trial including 
the written information given approval/favorable opinion by the Ethics Committee (IRB/IEC). 
Prior to a patient’s participation in the clinical trial, the Informed Consent Form should be 
signed and personally dated by the patient or by the patient’s legally acceptable representative, and 
by the person who conducted the informed consent discussion. 
The Informed Consent Form used by the Investigator for obtaining the patient’s informed 
consent must be reviewed and approved by the Sponsor prior to submission to the appropriate 
Ethics Committee (IRB/IEC) for approval/favorable opinion. 
Signed consent forms must remain in the Investigator file and must be available for verification 
by study monitors or authorized regulatory representatives at any time. 
The patient should receive a copy of the signed and dated written Informed Consent Form. Any 
amendments to the written information will be provided to the patients. 
3.8 
Premature Termination 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. Should 
this become necessary, the procedures will be agreed after consultation between the two parties. 
In terminating the study, the Sponsor and the Principal Investigator will ensure that adequate 
consideration is given to the protection of the best interests of the patients. 
3.9 
Definition of end of the trial  
End of trial in a Member State of the European Union is defined as the last visit (Visit 4, planned 
at the end of the 30-day follow-up period), of the last patient as defined in the protocol in all the 
concerned-Member State. Poor recruitment (recruiting less that the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but considered as normal 
conclusion to the study in that Member State.  


 
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4. Study Objectives and Investigational Plan 
The study objective is to assess the safety and the efficacy on the activity part of the SAF 
histological score (inflammation and ballooning) of a 24-week treatment with two doses of 
lanifibranor (800, 1200 mg/24h) in NASH adult patients. 
4.1 
Study Design 
The study is a three arm (placebo, lanifibranor 800 and 1200 mg/day), randomized (1:1:1), 
double-blind, placebo-controlled, multicenter, 24-week treatment study. 
The goal of the proposed study is to show improvement of cardinal NASH histopathologic 
features as well as safety data after a 6-month treatment. 
The study will require to randomize 225 NASH patients (i.e. at least 300 screened patients, see 
section 9.2 for sample size description). The overall study design is shown in Figure 1. 
Patients will undergo 6 visits: screening visit (V-1, -8 weeks to -2 weeks), randomization (V0), 
interim visit 1 (V1, 4 weeks after V0), interim visit 2 (V2, 10 weeks after V1), End of treatment 
visit (V3, 10 weeks after V2) and a follow-up visit (4 weeks after V3). A detailed list of procedures 
performed at each visit is presented in section 5. 
As the main efficacy goal of the study is to assess treatment effect on histologic features of 
NASH, there will be a centralized reading of slides of a liver biopsy to confirm the diagnosis and 
assess the severity at screeing phase (V-1) and end of treatment visit (V3). At the screening phase, 
the liver biopsy could either have been performed within 6 months before the screening period or 
performed during the screening process after confirmation of the patient eligibility regarding all 
others inclusion/exclusion criteria (incl. biological values, physical examination, ECG, FibroScan, 
and LMS in selected centers). The liver biopsy at the end of the treatment period will be performed 
as part of the visit 3 (week 24). 
Clinical and laboratory safety assessments will be performed at each visit. ECG will be 
performed at screening, interim visit 1 and end of treatment and will be read centrally. 
A FibroScan™ will be performed at screening and end of treatment visit to assess Transient 
Elastography (TE) and Controlled Attenuation Parameter (CAP). 
Inflammatory, glucose metabolism and lipid metabolism markers will also be assessed as well 
as exploratory biomarkers of NASH activity or PPARs agonist activities. 
 Screening Phase 
For the patients with a biopsy performed within 6 months before screening, all diagnostic tests 
regarding NASH (including a liver biopsy), HCV and the elimination of other causes of ALT 
elevation must have been performed before the patient would be considered for inclusion in the 
study as part of the routine medical care and will not be performed specifically for the study. 
The goal of the screening is therefore to check inclusion and exclusion criteria mainly by 
centralized reading of a previous liver biopsy and centralized laboratory tests. For Women with 
childbearing potential, a serum pregnancy test will also be performed (HCG testing) at the 
screening visit. 
The screening phase will be of at least of 10 working days, but of no more than 8 weeks, to 
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For the patients without liver biopsy performed within 6 months before screening, the liver 
biopsy will be part of the screening tests. However, to avoid unnecessary biopsies, the screening 
process should be performed according to the 3 sequential steps described below: 
Step 1:  Review of the medical history, concomitant medications, physical examination, 
electrocardiogram, biological sampling and FibroScan (mandatory). Patients will be 
withdrawn from the study at this step in case of TE > 12.5 kPa (i.e. high probability of 
cirrhosis). 
Step 2:  MRI/Liver MultiScan technology, only in selected sites. Patients will be withdrawn 
from the study at this step in case of LIF < 2 or MRI-PDFF 5% (see section 5.2.8). 
Step 3:  A liver biopsy will be performed. In all cases, liver biopsy will be performed upon 
medical indication and according to the standard practice of the site. 
After validation of the histological criteria by the central reading assessment, patients can be 
randomized. 
 Treatment Period 
At the randomization visit, 75 patients in each group will receive either placebo or lanifibranor 
800 mg/day or lanifibranor 1200 mg/day for 24 weeks. 
 Follow-up Period 
Safety of withdrawal from treatment groups is assessed during a 30-day assessment phase. 
 Patient management at the end of treatment 
The trial treatment is stopped after V3. 
After the follow-up period (V4, 4 weeks after V3) the Investigator/hepatologists/general 
practitioner will decide according to each patient, the need to use the lifestyle changes 
recommendations whenever appropriate and treatment of comorbidities which may play a role in 
NASH such as, for example, diabetes and hyperlipidaemia.  
If the study is positive there will be further trials for which these patients may be eligible. 
 Total study duration 
The total duration of the study is up to 38 months, i.e. at least 30 months of enrollment period 
and up to 8 months of patient participation. 
4.2 
Study Population 
 Inclusion Criteria 
 Adult subjects, age ≥18 years. 
 NASH histological diagnosis according to the currently accepted definition of both 
EASL and AASLD (62,66,67), requiring the combined presence of steatosis (any 
degree ≥ 5%) + lobular inflammation of any degree + liver cell ballooning of any 
amount, on a liver biopsy performed ≤ 6 months before screening in the study and 
confirmed by centralized reading during the screening period and 
a. SAF Activity score of 3 or 4 (>2) 
b. SAF Steatosis score ≥ 1  


 
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c. SAF Fibrosis score: < 4. 
 Subject agrees to have a liver biopsy performed after 24 weeks of treatment. 
 Compensated liver disease with the following hematologic and biochemical criteria 
before randomization: 
o ALT < 10xULN 
o Hemoglobin ≥ 110 g/L (11 g/dL) for females and ≥ 120 g/L (12 g/dL) for 
males 
o White blood cell (WBC) > 2.5 10^9/L (2.5 10^3/µL) 
o Neutrophil count > 1.5 10^9/L (1.5 10^3/µL) 
o Platelets > 100 10^9/L (100 10^3/µL) 
o Total bilirubin < 35 µmol/L (2.06 mg/dL). Patients with bilirubin ≥ 35 
µmol/L can be included if non-conjugated bilirubin in the setting of a 
Gilbert’s syndrome. 
o Albumin > 36 g/L (3.6 g/dL) 
o INR < 1.4 
o Serum creatinin < 115 µmol/L (1.3 mg/dL) (men) or < 97 µmol/L                
(1.1 mg/dL) (women) or estimated glomerular filtration rate ≥ 60 
mL/min/1.73m2 
 No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, 
HBV, HCV, Wilson’s, α-1-antitrypsin deficiency, hemochromatosis, etc…) considered 
to have an impact on the patient’s safety or on the efficacy evaluation. 
 If applicable, have a stable type 2 diabetes, defined as HbA1c ≤ 8.5% and fasting 
glycemia <10 mmol/L (180 mg/dL), no introduction of new medication in the 
previous 6 months, and no new symptoms associated with decompensated diabetes in 
the previous 3 months. Minor modifications of anti-diabetic treatments or dosages are 
allowed if done in a context of stable type 2 diabetes, i.e. HbA1c ≤ 8.5% in the 
previous 6 months. 
 Have a stable weight since the liver biopsy was performed defined by no more than a 
5% loss of initial body weight. 
 Negative pregnancy test or post-menopausal. Women with childbearing potential (i.e. 
fertile, following menarche and until becoming post-menopausal unless permanently 
sterile) must be using a highly effective method of contraception (i.e. combined 
(estrogen and progestogen containing) hormonal/ progestogen-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner). The 
contraceptive method will have to be followed for at least one menstruation cycle after 
the end of the study 
 Subjects having given her/his written informed consent. 
 Exclusion Criteria 
 Evidence of another form of liver disease considered to have an impact on the 
patient’s safety or on the efficacy evaluation. 
 History of sustained excess alcohol ingestion in the year before the pre-study 
treatment biopsy: daily alcohol consumption > 30 g/day (3 drinks per day) for males 
and > 20 g/day (2 drinks/day) for females. 


 
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 Unstable metabolic condition: Weight change > 5% in the last three months, diabetes 
with poor glycemic control (HbA1c > 8.5%), introduction of an antidiabetic or of an 
anti-obesity drug or restrictive bariatric (weight loss) surgery in the past 6 months 
prior to screening. 
 History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or 
ingestion of drugs known to produce hepatic steatosis including oral corticosteroids 
(at dose >5mg/day prednisone equivalent), estrogens (at doses greater than those used 
for hormone replacement or contraception), tamoxifen, methotrexate, tetracycline or 
amiodarone in the previous 6 months. Corticosteroids administered by routes other 
than oral are allowed. One short (<2 weeks) course of oral corticosteroids, more than 
3 months before the pre-study treatment biopsy is also allowed. 
 Significant systemic or major illnesses other than liver disease, including congestive 
heart failure (class C and D of the AHA), unstable coronary artery disease, 
cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, 
serious psychiatric disease, malignancy that, in the opinion of the Investigator, would 
preclude treatment with lanifibranor and/or adequate follow up. 
 HBs antigen >0, HCV PCR >0 (patients with a history of HCV infection can be 
included if HCV PCR is negative since more than 3 years), HIV infection. 
 Pregnancy or lactation or inability to adhere to adequate contraception in women of 
child-bearing potential. 
 Active malignancy except cutaneous basocellular carcinoma. 
 Any other condition which, in the opinion of the Investigator would impede 
competence or compliance or possibly hinder completion of the study. 
 Body mass index (BMI) >45 kg/m2. 
 Type 1 diabetes and type 2 diabetic patient on insulin. 
 Diabetic ketoacidosis  
 Fasting Triglycerides > 300 mg/dL (3.39 mmol/L). 
 Hemostasis disorders or current treatment with anticoagulants. 
 Contra-indication to liver biopsy. 
 History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease 
event, including myocardial infarction, except patients with only well controlled 
hypertension. Any clinically significant ECG abnormality reported by central ECG 
reading confirmed by the Investigator to be Clinically Significant. 
 Participation in any other investigational drug study within the previous 3 months. 
 Have a known hypersensitivity to any of the ingredients or excipients of the IMP 
including: Lactose monohydrate, Hypromellose, Sodium laurilsulfate, Sodium starch 
glycolate (type A), Magnesium stearate, Opadry™ II 85F18422 
 Be possibly dependent on the Investigator or the Sponsor (e.g., including, but not 
limited to, affiliated employee). 
 Creatine phosphokinase (CPK) >5 x ULN 


 
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 Patient with history of well documented osteopenia. Patient treated with vitamin D 
and/or Calcium based supplements for preventive reasons can be included. 
(The criteria below are applicable only for patients who will undergo a MRI/LMS in selected 
centers) 
 Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. 
Sedation is permitted at discretion of Investigator. 
 Metallic implant of any sort that prevents MRI examination including, but not limited 
to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural 
stimulator, metallic contraceptive device, tattoo, body piercing that cannot be 
removed, cochlear implant; or any other contraindication to MRI examination. 
 
 Prohibited concomitant medications 
If not specified, the following treatment must be stopped at the latest before randomization 
 PPAR Gamma agonists, PPAR Alpha agonists (fibrates), ezetimibe 
 Bile salts chelators, phytosterols, fish oils, 
 Glucagon like peptide-1 receptor agonists (incl. litaglutide, exenatide),  
 Insulin, 
 Vitamins E (alpha-tocopherol), 
 Anticoagulants (incl. warfarin, dabigatran, rivaroxaban, apixaban), 
 Oral corticosteroids.  
 
 Allowable medications for standard care or precautions 
 Obesity: stable weight since the liver biopsy was performed, defined by no more than a 
5 % loss of initial body weight (cfr inclusion criteria 7). 
 Treatment used for the underlying medical condition 
Treatments are allowed within certain restrictions (described above and below) and 
provided they have been kept at stable doses for at least 6 months before the pre-
treatment biopsy. 
Type 2 diabetes:  
 Metformin,  
 Dipeptidyl peptidase-4 inhibitors,  
 Sodium-glucose transport protein 2 inhibitors: canagliflozin, dapagliflozin and 
empagliflozin.  
Minor modification of anti-diabetic treatments or dosages are allowed if done in the context of 
stable type 2 diabetes, i.e. HbA1c ≤8.5% in the previous 6 months. 
 


 
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Hyperlipidemia: only statins at stable doses within the past 3 months before pre-study 
treatment biopsy will be allowed. 
Antiplatelets agents: The antiplatelets agents (incl. low-dose aspirin, ticlopidine, 
clopidogrel, prasugrel, ticagrelor) are allowed. 
Herbal supplements and Others Supplementation: Herbal preparations or vitamin 
supplements with no exact composition known should not be started during the 
course of the study as they could be liver toxic. 
 Other Medications  
Medications other than the IMP and those mentioned above should only be started during 
the course of the study with the agreement of the Investigator in order to avoid 
interference with study assessments. The need for other medication may lead to exclusion 
of the patient from the study.  
If symptomatic medication is needed to treat adverse events related to IMP, the 
Investigator will inform the Sponsor about the concomitant medication given. 
 Enrolment 
If a patient is not eligible, the main reason for non-inclusion will be documented in the source 
document and the screening log. After eligibility is confirmed, patients will be assigned a treatment 
number. Treatment numbers will be allocated in ascending order, the order in which patients are 
included. The Investigator or a staff member will enter the patient initials and number in a web-
based electronic Case Report Form (eCRF), the confidential patient identification list and the drug 
dispensing log. 
4.3 
Study Medication 
 Identity of Investigational Medicinal Product(s) (IMP) 
The lanifibranor tablets and Placebo To Match (PTM) are white to off-white, ovale shape, bi-
convex, film-coated tablets: 
 Each active tablet contains 400 mg of the active substance lanifibranor in an immediate 
release formulation. The chemical name of the active substance is 1-(6-
benzothiazolylsulfonyl)-5-chloro-1H-indole-2-butanoic acid. 
 The placebo tablet contains a physical mixture of lactose monohydrate, microcrystalline 
cellulose, and sodium starch glycolate and magnesium stearate. 
 Treatments Administered 
This double blinded placebo controlled study involves a therapeutic dose of 800 mg lanifibranor 
(qd) and 1200 mg lanifibranor (qd). 
The lanifibranor tablets and PTM are packaged into High-density polyethylene (HDPE) bottles 
of 100 ml (38 tablets for a treatment period of one month, plus a use margin of 1 week) with proper 
closures fitted with a silicagel cartridge. Three bottles each (either active or placebo) and labelled 
A, B and C with a colored circle sticker are assembled in a carton to compose monthly Kits as 
detailed below: 
- 
Placebo Kit: Morning (P+P+P) 
- 
800 mg Kit: Morning (P+A+A) 


 
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- 
1200 mg Kit: Morning (A+A+A) 
Where P denotes the placebo tablet and A denotes the active tablet (400 mg). 
Figure 4: IMP Packaging 
 
A total of 5 Patient Kits is representing the treatment per patient for the clinical study. 
 Medication Dispensing 
The patients receive at each visit one kit per month (i.e one kit at V0, and 2 kits at V1 and V2). 
They are instructed to take morning 3 tablets with food, i.e. one tablet from each of the containers 
A, B, and C. The overall treatment duration is 24 weeks. 
Dosage modifications are not permitted. Should the patient or the Investigator for any reason 
wish to discontinue treatment, they may do so at any time. The date of the last dose and or any 
dosage modifications by the patient are documented in the eCRF. 
 Selection and timing of Dose for Each Patient 
The treatment arm will be determined by a centralized electronic randomization at the inclusion 
visit. 
 Labeling 
Packaging and labelling is performed by Amatsi group, 17 Rue des Vautes, 34980 Saint-Gély-
du-Fesc, Tel: +33 (0) 4 99 58 38 60. 
The immediate containers (bottles) and the outer packaging (medication boxes) will contain the 
information required by national regulations as described in the requirements of Directive 
2003/94/EC. 
 
 


 
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Table 5: Summary of Labelling Details 
 Accountability 
The Investigator will maintain accountability records showing the quantities of IMP received 
at the study site and dispensed to each patient. Any unused IMP, including empty or partially used 
containers, will be accounted for and then destroyed. At the time of return to the Sponsor, the 
Investigator must verify that all unused or partially used investigational medicinal product supplies 
have been returned by the clinical study subject and that no remaining supplies are in the 
Investigator's possession. 
 Treatment Compliance 
The following means will be taken to improve compliance to treatment: 
 the Investigator will attempt to select patients able to understand and to comply with 
instructions, 
 the patient should be instructed to return containers at the end of the treatment period, 
 remaining tablets will be counted /recorded in the eCRF by sites and monitored by the 
Clinical Research Associate  
 Return or destruction of investigational products 
The products are collected by the Sponsor at the end of the study and are thereafter destroyed. 
Pharmaceutical dosage form 
38 tablets of Lanifibranor 400 mg or Placebo to Match. For Oral 
Use 
Batch N°:  
XXXX 
Bottle ID:  
XXXX 
Kit N°:  
XXXX 
Protocol ID:  
IVA_01_337_HNAS_16_002 
Sponsor:  
Inventiva SA, 50, rue de Dijon, 21121 Daix, France 
Telephone: +33 3 80 44 75 00 
Direction for Use:  
Take 3 tablets by mouth once daily with food (morning), one from 
bottle A, one from bottle B, and one from bottle C. 
For Clinical Trial Use Only 
Return all empty bottles or unused medication to the trial Centre at 
the next visit. 
Storage : 
Store in original container at 25°C or below. Do not freeze. 
Expiry Date:  
MM/YYYY 
Keep Out of Reach of Children. 
Caution*: New Drug – Limited by Federal (or United States) law to investigational use.  
* for US only 


 
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5. Measurements Assessed and Study Flow Chart 
The following section presents the assessments performed at each visit. Target dates are ± 3 
days. 
5.1 
Table of study procedures and assessments 
A table is provided in the schedule of Study Procedures (see Table 1 and Table 2). 
5.2 
Specific procedures for Assessment of outcomes 
 Liver Biopsy 
For each patient, five slides of a liver biopsy have to be sent for a central reading assessment, 
at screening for the validation of the histological inclusion criteria, and at visit 3 for the evaluation 
of the efficacy evaluation. 
At screening visit (V-1), if no slides are available from a liver biopsy performed within the past 
six months, a liver biopsy will be performed as part of the screening process after having checked 
that all non-histological inclusion/exclusion criteria are validated (i.e. biological values, ECG, 
Fibroscan and LMS if applicable).  
At end-of-treatment visit (V3), a liver biopsy is performed. 
o Procedures recommendation 
The liver biopsy will be performed according to each site local procedures and the 
recommendation below. 
A large needle (>19G), preferentially 16G, should be used in order to obtain biopsy samples 
that meet the quality requirements for accurate diagnosis.  
Where applicable, antiplatelets agents (i.e. aspirin, ticlopidine, clopidogrel, prasugrel, 
ticagrelor) will be stopped 10 days before the liver biopsy and will be resumed after 48-72 hours 
as per guidelines (68). After the procedure, each patient will be monitored during a minimal 
observation period of 4 hours or more depending on local practices. After discharge from hospital 
and for a minimum of 48 hours after the liver biopsy, patients will be instructed not to lift heavy 
weights (68). 
o Slides preparation and shipment 
Fixation and paraffin embedding of the biopsies will be performed according to local procedure 
and according to precautions detailed in Appendix C. 
Five slides have to be sent to BARC central laboratory for a quality control and staining (if 
requested, see Appendix C for details). The handling of the sample must be prepared and provided 
with the supplied kit by the Sponsor. Afterwards, the slides will be shipped without delay to 
Liverpat for the central reading.  
All biopsy slides will be stored at the Central pathologist department until the end of the study 
and then send back to sites by the central laboratory. Upon Investigator’s request, the biopsy slides 
might be sent back to the site on an ongoing basis. 
 Urine samples 
Urine Samples will be collected at V0 (including urine pregnancy test), V2, V3 and V4. Urine 
analysis by dipstick evaluating hematuria will be done on site. Urine samples will then be stored 
for further assessment and/or for safety evaluation. Urine specimens will be obtained by providing 


 
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participants with a collection cup and instructions for collecting as described in the sampling kit 
supplied by the Sponsor via the central laboratory. 
Safety assessments may be performed on the urine samples in case of renal function impairment 
is observed during the study. Albuminuria and other biomarker like cystatin C will be tested, and 
aliquots of urine samples will be stored in case where a urine biomarker specific of NASH is 
validated during the study. 
The tube labels need to contain the following information: Study Site, Subject Number, Day, 
Time, Visit number 
All urines samples will be destroyed by the central laboratory at the end of a scheduled storage 
period (1 year after the end of the study). 
 Blood samples taken 
Blood sample taken are performed at every visit, i.e. V-1 (screening) to V4 (Follow-up). The 
patient must be fasting overnight from 10:00 pm. Alternatively, blood sampling can be performed 
in the afternoon provided patients have been fasting for at least eight hours.Total blood volume 
sampled during the study for each patient (for pharmacokinetics, biomarkers, safety and efficacy 
biological tests) will be as follows: 
Table 6 : Blood volume taken at each visit per type 
Total Blood 
volume per Sample 
Type (mL) 
Screen 
Re-test* 
V0 
V1 
V2 
V3 
V4 
Total 
Serum (SST) 
8.5 
8.5 
34 
8.5 
8.5 
34 
8.5 
102 
Whole Blood 
(EDTA) 
3 
3 
6 
3 
3 
3 
3 
21 
Plasma (EDTA) 
- 
- 
3 
- 
- 
3 
- 
6 
Plasma (Citrated) 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
16.2 
Plasma (Fluoride-
oxalate) 
2 
2 
2 
2 
2 
2 
2 
12 
Plasma (Lithium 
Heparin) 
- 
- 
 
3 
- 
3 
- 
6 
Total Blood 
Volume per visit 
(mL) 
16.2 
16.2 
47.7 
19.2 
16.2 
47.7 
16.2 
179.4 
*if screening period > 4 weeks 
Attention must be paid to the kind of blood sample required (Biobank, Safety, 
Pharmacokinetics) as they vary between visits. 
For the monitoring of the individual subject, each samples should be collected under the same 
conditions (e.g. time ± 1h) as the baseline sample. This is to overcome the effects of the circadian 
variation of the biomarkers measured. 


 
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The samples need be collected at the clinical sites within 48 hours and shipped on dry ice. The 
tube labels need to contain the following information: Study Site, Subject Number, Day, Time, 
Visit number, Aliquot number, Sampling times and dates also need to be recorded on the eCRF. 
The central laboratory needs be notified of a shipment at least 3 days prior to shipment arrival. 
The notification should include the study number, the number of samples, the Airway Bill Number, 
the estimated time of arrival (ETA) and an electronic sample list. 
More detailed instructions for handling and preparing the samples are provided with the kit 
supplied by the Sponsor via the central laboratory. 
All blood samples will be destroyed by the central laboratory at the end of a scheduled storage 
period (1 year after the end of the study). 
  Waist measurement 
The Waist measurement must be done at midway between the top of the hip bone and the bottom 
of the ribs during a normal breath-out (Appendix B). 
 Electrocardiogram  
12-lead ECGs will be performed at Screening (V-1), interim visit 1 (V1) and the end-of-
treatment visit (V3) and a central assessment will be performed by a specialized CRO.  
Two originals ECGs print out using an A4 format (no photocopies) have to be recorded in order 
to send a blinded one to the CRO (attached with a transmission Form), the second one to be keep 
in patient’s medical file. 
Please refer to Appendix B for the detailed technical procedure. 
 Vital signs 
Blood pressure will be measured by using a sphygmomanometer. The results will be recorded 
in millimeters of mercury (mmHg). Pulse rate will be measured for 30 seconds and will be recorded 
as beats/minute. Blood pressure and pulse will be measured lying after at least a 10-minute rest. 
 Fibroscan® 
A Fibroscan® will be performed at screening visit and end of treatment visit (V3), if available. 
In case of no historical slides from a liver biopsy performed within 6 months prior the screening 
process, Friboscan® will be mandatory before scheduling a liver biopsy.  
TE and CAP will be evaluated by using Fibroscan® technology. Fibroscan® is a totally non-
invasive and completely painless ultrasound technique that will not require the use of anaesthesia 
or sedation. Any size of probe (M, XL) can be used, but it will have to be reported in the eCRF. 
TE is an approved parameter for the diagnosis of cirrhosis in patients with chronic liver diseases. 
In this study, an optimal cut-off of 12.5 kPa (patients with TE>12.5 kPa) will be set for the 
discrimination of cirrhotic patients (with negative predictive value higher than 90%) as defined in 
the Non-invasive tests for liver disease diagnosis guidelines (69).  
If available at site, CAP (expressed in dB.m-1) will be recorded in the eCRF. CAP has the ability 
to quantify and detect hepatic steatosis from 10% of fatty infiltration and is not influenced by liver 
fibrosis and cirrhosis (70–73). 


 
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 Liver Multiscan 
Where available, the subject’s liver will be evaluated using LiverMultiScan (non-invasive MRI 
technology). LiverMultiScan (LMS) is non-invasive and completely painless magnetic resonance 
technique that will not require the use of anaesthesia, sedation or contrast injection. The imaging 
protocol takes just 10 minutes, in which parametric maps are taken of the liver, using quantitative 
imaging. This will allow the study doctor to measure the levels of fat, iron and fibroinflammatory 
disease.  
The quantitative images taken using MR based LiverMultiScan technique will be used to 
measure 1) hepatic iron content, measured by T2* (ms) and presented as mg/g of dry weight liver, 
2) hepatic fat content, measured by IDEAL (MRI-PDFF) and presented as %, and 3) cT1 or iron-
corrected T1 that correlates with liver fibrosis and inflammation, derived by an algorithmic 
correction of T1 (ms) by T2* and presented in ms. cT1 is additionally reported as Perspectum 
Diagnostics’ proprietary metric, the Liver Inflammation and Fibrosis (LIF) score. An MRI-PDFF 
cut-off of >5% indicates hepatic steatosis, and in this study, a cutoff of LIF <2 will be set to rule 
out subjects without significant fibroinflammatory disease (eg NASH). Consider biopsy for 
subjects with LIF≥2 and MRI-PDFF >5%. 
This cT1 metric is standardized across all MRI manufacturers, and presented as the LIF score 
for easy patient and physician communication. Conditions which increase the extracellular fluid 
content, such as inflammation and fibrosis, cause a higher LIF score and the LIF score has been 
shown to predict clinical outcomes in patients with chronic liver disease, as well as correlating 
with biopsy. 
Multiparametric MR is a tool for the evaluation of patients with NAFLD/NASH that provides 
reliable data more frequently compared to transient elastography, with no differences in the 
diagnostic accuracy for significant fibrosis or cirrhosis. Furthermore, multiparametric MR has 
good accuracy for the diagnosis of NASH and ballooning. The particular strength of the MR 
technique is the ability to assess both the necro-inflammatory and fibrotic components of NASH 
in a single test that allows accurate evaluation of the overall disease severity (74). 
 Quality of Life questionnaire 
SF-36: The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 
8-scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures and a preference-based health utility index 
(http://www.sf-36.org/tools/sf36.shtml, Appendix D).  
FFS: The Flinders Fatigue scale (FFS) is a self-report questionnaire assessing daytime fatigue 
related to poor sleep. It is a relatively brief measure, containing only 7 items that provide a global 
measure of fatigue (http://dspace.flinders.edu.au/xmlui/handle/2328/10181, Appendix E) 
The patient’s information sheet and the patient questionnaires are provided in the local 
language. The Investigator and medical staff are available for explanations and questions, at the 
visit and via telephone thereafter. 
5.3 
Procedures at each visit 
 Screening (V-1) 
As part of the patient's direct clinical care team, only the referent doctor will be able to invite 
potential patients to participate to the study according to his/her patient medical records. The 
referent doctor will go through the information sheet and answer any questions that the patient 


 
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may have. The patient will also have the ability to discuss his/her participation with family, friends 
or family doctor (general practioner: GP). 
The patient will be asked to sign and date the attached “Patient Informed Consent” form, prior 
to any study procedure being performed. 
The pre-treatment procedures are listed in the Schedule of Study Procedures (Table 1). Details 
are provided in section 5.2 of the protocol and in the eCRF.  
Blood sampling: Kits with supplies and instructions are provided for the safety blood sampling 
and a serology test to exclude HIV infection will also be performed. 
Fibroscan®: This exam is mandatory if a liver biopsy is done at screening, in order to avoid 
this procedure in patients with high risk of cirrhosis. 
Liver Multiscan: This exam is mandatory in selected centers to assess patient’s eligibility to the 
liver biopsy (if not performed within the past 6 months). 
Electrocardiogram: An ECG has to be performed and centrally assessed to validate inclusion 
and exclusion criteria. 
Liver Biopsy: for the patients who do not have a liver biopsy performed within 6 months before 
screening. 
Liver Biopsy Centralized Reading: Details on how to perform the reading of the liver biopsy 
are provided in Section 5.2.1.  
Safety: Any untoward medical event, which occurs from the time of signed Informed Consent 
to the time of first IMP administration, will be classified as “non treatment-emergent AE 
 Retest visit (additional visit during screening process) 
A retest visit could be performed if requested by Investigators and/or Sponsor to 
confirm/invalidate abnormal biological values at screening process. This retest will be mandatory 
if the total duration of the screening period exceed 4 weeks (i.e. inclusion/non-inclusion criteria 
related to safety laboratory tests have to be checked with results of less than 4 weeks before 
randomization). 
The randomization could be done only after receipt of the retest reports and validation of the 
results by the Investigators and/or Sponsor Referent Physician. 
 Randomization and Beginning of the Treatment Period (V0) 
At this visit, the eligibility of the patient is confirmed, and the treatment starts.  
The assessments to be performed are listed in the Schedule of Study Procedures (Table 1). 
Blood sampling: Kits with supplies and instructions are provided for the safety, efficacy, 
biobank, pharmacokinetics and genotype blood sampling as early as possible in the morning. 
Blood samples will be taken in the morning after overnight fasting. The patient must be fasting 
overnight from 10:00 pm. Alternatively, blood sampling can be performed in the afternoon 
provided patients have been fasting for at least eight hours.  
Safety: AEs that have occurred since the last visit are recorded, irrespective of a potential 
relationship with the concomitant background treatment. Please observe the reporting 
requirements for AEs (see Section 6). 


 
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Randomization: The randomization code is provided through an online system after 
identification with a login and a password. Once some details are entered, the system lets you know 
immediately, which medication kit to use for this particular patient.  
Treatment: The patient receives one monthly kit (packaging described in Figure 4), and they are 
carefully instructed how to take the drug and the importance of bringing back to the site the 
unused medication at each visit. Patients need to take morning 3 tablets with food, i.e. one tablet 
from each of the containers A, B, and C. 
The date of the next visit in 4 weeks is agreed. The time window for the visits is +/- 3 days. 
 Intermediate Study Visit 1 to Visit 2 (V1, Week 4 and V2, Week 14) 
Important: Please note that the visits are not at regular intervals and the assessments vary. 
The assessments to be performed are listed in the Schedule of Study Procedures (Table 1).  
Treatment: It is therefore important to ensure each time, that the patient has sufficient 
medication until the next visit. It may be necessary to distribute 2 monthly kits to cover the time 
to the next visit. The last distribution takes place on Visit 2. Patients are carefully instructed how 
to take the drug and the importance of bringing back to the site the unused medication, so that drug 
accountability can be verified and completed.  
Blood sampling: Kits with supplies and instructions are provided for the safety and efficacy 
blood sampling. 
Electrocardiogram (only at V1): An ECG has to be performed and centrally assessed to evaluate 
the safety of the patients. 
The patients withdrawn early from the study should, if at all possible, undergo the Visit 3 
assessments and procedures. 
Please observe the reporting requirements for AEs (see Section 6). 
 End of Treatment Visit or withdrawal (V3, Week 24) 
Visit 3 is the therapy-end visit.The assessments to be performed are listed in the Schedule of 
Study procedures (Table 1). 
Blood sampling: Kits with supplies and instructions are provided for the safety, efficacy, 
Biobank and pharmacokinetics blood sampling. 
Fibroscan®: The parameters recorded will be correlated to those obtain with the liver biopsy 
performed at the end of treatment. 
Electrocardiogram: An ECG has to be performed and centrally assessed to evaluate the safety 
of the patients. 
Liver biopsy: Details on how to perform the biopsy are provided in Section 5.2.1. 
Please observe the reporting requirements for AEs (see Section 6). 
Important: In case of early withdrawal, the following (i.e. follow-up post-treatment visit, 4 
weeks after the end of treatment) should also be performed whenever possible.  
 Follow-up Post-Treatment Visit, End of Study Visit (V4, Week 28) 
A follow-up visit takes place 4 weeks after the end of treatment. The assessments to be 
performed are listed in the Schedule of Study Procedures (Table 1). 


 
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Blood sampling: Kits with supplies and instructions are provided for the safety and efficacy 
blood sampling.  
Please observe the reporting requirements for AEs (see Section 6). 
 Unscheduled/safety Visits 
During the all treatment and the follow-up period, the Investigator may conduct unscheduled 
visit that may perform again study procedures, including vital signs assessments, blood sample 
taken and physical examination. These visits will have to be motivated by the Investigator in the 
aim of guarantee the safety of the patients. 
Specific events listed bellow, will automatically generate an Unscheduled/safety visit: 
- 
ALT increase of 2 times of the baseline value at V0: A safety visit has to be performed 15 
days later. A blood taken will be performed to check the ALT level. 
- 
ALT increase of 5 times the upper limit of the normal range (ULN): A safety visit has to 
be performed 15 days later. A blood taken will be performed to check the ALT level 
Please refer to paragraph 10 for withdrawal criteria. 
6. Safety Assessment  
6.1 
Adverse Events 
 Definitions accroding to ICH guidelines 
o Adverse event: Any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to the IMP. 
o Adverse reaction of an IMP: All untoward and unintended responses to an investigational 
medicinal product related to any dose administered. 
All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship (i.e. possible/probable) to a medicinal product qualify as adverse 
reactions. The expression reasonable causal relationship means to convey in general that there is 
evidence or arguments to suggest a causal relationship. 
 Collection 
The condition of the patients will be monitored throughout the study. Subjective symptoms 
reported spontaneously by the patient as well as signs observed by medical staff will be recorded 
in the source records and the eCRF. 
Any AE (including laboratory test abnormalities, intercurrent illnesses or injuries, and/or study 
procedures related AE) reported spontaneously by the subjects, or observed by the Investigator, 
will be recorded in the trial database. 
Any untoward medical event, which occurs from the time of signed Informed Consent to the 
time of first IMP administration, will be classified as “non treatment-emergent AE”. 
 Intensity Rating 
The intensity of an AE will be rated as follows: 


 
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- 
Mild: no interference with the subject’s daily activities and does not require mandatory 
corrective/symptomatic treatment. 
- 
Moderate: moderate interference with the subject’s daily activities and/or requires minimal 
medical intervention or corrective treatment required. 
- 
Severe: major and unacceptable interference with the subject’s daily activities and requires 
mandatory corrective/symptomatic treatment, possible hospitalization. 
 Causality Rating 
The causal relationship of an AE to the IMP will be rated as follows: 
- 
Unrelated: Clearly and incontrovertibly due only to extraneous causes, and does not meet 
criteria listed under unlikely, possible or probable. 
- 
Unlikely: Does not follow a reasonable temporal sequence from administration of the IMP, 
or is most likely related to another etiology than the trial drug such as the patient’s clinical 
state, environmental factors or other therapies. 
- 
Possible: Follows a reasonable temporal sequence from administration of the IMP, and/or 
a causal relationship cannot be excluded and remains likely.  
- 
Probable: good reason (such as clear-cut temporal association with improvement on 
cessation of the IMP or reduction in dose, or reappears upon (accidental) rechallenge, or 
follows a known pattern of response to the IMP) and sufficient documentation to assume a 
causal relationship. 
 Action Taken 
The action taken with the IMP for an AE will be rated as product withdrawn, temporary 
interruption, or dose not changed. AEs requiring therapy will be treated with recognized standards 
of medical care to protect the health and the well-being of the patient. 
 Outcome 
The outcome of an AE will be rated as recovered, recovering, sequelae, not recovered, fatal or 
unknown. The Investigator will follow up any AE until it is resolved or until the medical condition 
of the patient is stable. All relevant follow-up information will be collected.  
For AEs that are ongoing at the last visit, the Investigator will make thorough efforts to 
document the outcome in the eCRF, until 28 days after end of study treatment for AEs considered 
by the Investigator as unrelated or unlikely related to study treatment, and until the database lock 
for AEs considered by the Investigator as possibly or probably related to the study treatment. 
 Multiple Signs or Symptoms 
If an AE consists of several signs or symptoms that can be represented by one single syndrome 
or diagnosis, the syndrome or diagnosis will be recorded in the eCRF as the AE instead of the 
individual signs or symptoms. 
 Worsening Signs 
Symptoms, syndromes or diagnoses present before the first administration of the IMP will be 
considered as AEs if they worsen after the start of the IMP. 


 
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6.2 
Serious Adverse Events or Reactions 
 Definitions 
A Serious Adverse Event (SAE) is any untoward medical occurrence or effect that at any dose: 
 results in death; 
 is life-threatening (at the time of the event); 
 requires in patient hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity; 
 is a congenital anomaly/birth defect; 
 or is an important medical event. 
Death: the death of a patient enrolled in a clinical study is per se not an event, but an outcome. 
An AE resulting in a fatal outcome must be fully documented and reported, including if the death 
occurred after treatment end, and regardless of the causality relationship of the death to the IMP. 
The cause of the death is usually the AE. If the cause cannot be determined, the case will be 
considered an unexplained death. 
Life-threatening: an AE that places the patient, in the view of the initial reporter (Investigator), 
at immediate risk of death from the AE as it occurred, i.e. it does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
Hospitalization: an AE requiring an unplanned inpatient hospital admission, including at least 
an overnight stay. Of note: when standard practice for liver biopsy requires overnight 
hospitalization, this shall not be considered as an adverse event. 
Disability: a substantial disruption of a person’s ability to conduct normal life functions. 
Important medical event: an important medical event that may not result in death, be life-
threatening, or require hospitalization may be considered as a SAE when, based upon appropriate 
medical judgement, it may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition. The concept includes AEs which suggest a 
significant hazard, contraindication or precaution for use, occurrence of malignancy or 
development of drug dependency or drug abuse. 
Overdose: an overdose of an IMP is the accidental or intentional administration of a dose higher 
than the highest dose under clinical investigation. An overdose will be documented and reported 
to the safety officer (SO) in the same way as a SAE even if no toxic effects were observed. 
Pregnancy: The occurrence of a pregnancy of a study patient or a partner of a study patient 
discovered during IMP administration or within 1 week after last administration of the IMP, is to 
be communicated to the Sponsor in an expedited manner with the same procedure and timelines 
as for SAEs (see section 6.2.2), independently from the occurrence of an AE. Specific follow-up 
of the event will be requested by the Sponsor until pregnancy outcome, at least on a quarterly basis 
as described in paragraph 10.1. 
 Immediate reporting 
The Investigator will immediately, i.e. within 24 hours from first knowledge, report any SAE 
occurring during the study to the safety officer (SO) acting on behalf of the Sponsor of the study: 


 
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STRAGEN SERVICES S.A.S, 52 rue de la République, 69002 Lyon, France 
Tel: +33 (0) 4 78 42 95 26, fax: +33 (0) 4 78 42 55 71, 
Email:  
The Investigator will complete in English and sign a SAE Report Form and transmit it to the 
SO by email or telefax not later than 24 hours after the first knowledge of the SAE. The SO 
acknowledges the receipt of the SAE information by email to the investigational site within one 
working day. In the absence of email acknowledging the receipt or in case of issue in sending the 
fax or email, the Investigator shall contact the SO by any means for ensuring the receipt of SAE 
information at the earliest opportunity. 
Any follow-up information will be reported to the SO and to the Sponsor as soon as it becomes 
known, with the same process and timelines as described here above for initial reports. As per 
Article 17 of the European Directive 2001/20/EC, the Sponsor will ensure that all relevant 
information about SAE and suspected serious unexpected adverse reactions (SUSAR) is recorded 
and reported to the national CA in all Member States concerned and to Ethics Committee within 
the applicable timeframe. 
Serious adverse events occurring after the last study visit will only be reported if the Investigator 
believes that the event may have been caused by the IMP or a protocol procedure. 
Hospitalization for a diagnosis or therapeutic procedure planned before study enrolment but 
performed after the enrolment should not be considered for SAE and should be reported in eCRF 
in concomitant procedures page. 
6.3 
Safety Variables 
All safety variables will be primary ones. Safety evaluations will be completed as given in 
section 9.7 and as indicated below. 
The Investigator will rate all safety variables as to clinical relevance or not. In case of a 
clinically relevant abnormality, the safety evaluation will be repeated. If the abnormality is 
confirmed and clinically relevant, it will be recorded as an AE term in the eCRF. The abnormality 
will be followed up until the value has returned to normal or an adequate explanation is found. 
 Physical Examination 
Physical examinations will be conducted by the Investigator. Any findings will be documented 
in the source document and recorded in the eCRF. 
 Laboratory Tests 
Laboratory tests will be analyzed by a central laboratory (CL). In the aim of maintining the 
“double-blind”, some biological values will be blinded on Central laboratory reports/records until 
the end of the study and could be unblinded only on DSMB members request. In this case, an 
independent data-management team will be indetify at KEYRUS BIOPHARMA to perform the 
data-transfert of theses biological value. 
Additional samples for laboratory safety variables may be drawn at any time during the study 
at the Investigators judgement. The laboratory assessments performed at each visit are listed in the 
following table (see Table 7 and Table 8). 
 


 
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Table 7 : Central laboratory tests for safety assessment 
Domain 
Goal 
Test 
Screen V0 
V1 
V2 
V3 
V4 
Bone 
Safety 
B-Crosslaps 
- 
 
- 
- 
 
- 
Safety 
Osteocalcin 
- 
 
- 
- 
 
- 
Chemistry 
 
Safety 
Creatinine 
 
 
 
 
 
 
Safety 
CPK 
 
 
 
 
 
 
Safety 
Urea 
 
 
 
 
 
 
Safety 
Albumin 
 
 
 
 
 
 
Hematology 
 
Safety 
Hb 
 
 
 
 
 
 
Safety 
RBC 
 
 
 
 
 
 
Safety 
Platelets 
 
 
 
 
 
 
Safety 
WBC (Diff Count) 
 
 
 
 
 
 
Safety 
MCV 
 
 
 
 
 
 
Safety 
CCMH 
 
 
 
 
 
 
Safety 
Hematocrit 
 
 
 
 
 
 
Safety 
Reticulocytes 
 
 
 
 
 
 
Inflammation Safety 
Nt-ProBNP 
- 
 
- 
- 
 
- 
liver 
Safety 
INR 
 
 
 
 
 
 
 


 
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Table 8 : Central Laboratory tests for efficacy assessment 
Domain 
Goal 
Test 
Screen 
V0 
V1 
V2 
V3 
V4 
Efficacy 
TIMP-1 
- 
 
- 
- 
 
- 
Efficacy 
TIMP-2 
- 
 
- 
- 
 
- 
Efficacy 
cytokeratin K18 
- 
 
- 
- 
 
- 
Efficacy 
hyaluronic acid 
- 
 
- 
- 
 
- 
 
Efficacy 
P3NP 
- 
 
- 
- 
 
- 
Fibrosis 
Efficacy 
FGF 21 
- 
 
- 
- 
 
- 
Glucids 
Efficacy 
Insulin 
- 
 
- 
- 
 
- 
Efficacy 
Fasting glucose 
 
 
 
 
 
 
Efficacy 
HbA1c 
 
 
 
 
 
 
Efficacy 
peptide C 
- 
 
- 
- 
 
- 
Efficacy 
fructosamine 
- 
 
- 
- 
 
- 
Chemistry 
Efficacy 
Plasma Iron 
 
- 
- 
- 
 
- 
Efficacy 
Transferrin 
 
- 
- 
- 
 
- 
Efficacy 
Ferritin 
 
- 
- 
- 
 
- 
Inflammation 
Efficacy 
Fibrinogen 
- 
 
- 
- 
 
- 
Efficacy 
hs-CRP 
- 
 
- 
- 
 
- 
Efficacy 
Alpha2-macrogulin 
- 
 
- 
- 
 
- 
Efficacy 
Haptoglobin 
- 
 
- 
- 
 
- 
Lipids 
Efficacy 
Triglycerides 
 
 
 
 
 
 
Efficacy 
HDL-C 
 
 
 
 
 
 
Efficacy 
LDL-C 
 
 
 
 
 
 
Efficacy 
Total-C 
 
 
 
 
 
 
Efficacy 
FFA 
- 
 
- 
- 
 
- 
Efficacy 
APO A1 
- 
 
- 
- 
 
- 
Efficacy 
Adiponectin 
- 
 
- 
- 
 
- 
Efficacy 
Leptin 
- 
 
- 
- 
 
- 
Liver 
Efficacy 
ALT 
 
 
 
 
 
 
Efficacy 
AST 
 
 
 
 
 
 
Efficacy 
AlcPhos 
 
 
 
 
 
 
Efficacy 
Bilirubin total 
 
 
 
 
 
 
Efficacy 
GGT 
 
 
 
 
 
 
 


 
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 Vital Signs 
Vital signs will be assessed at each visit including the screening visit and from V0 to V4. Please 
refer to section 5.2.6 for the detailed technical procedure. For methods and normal values 
definition, see Appendix B 
 Electrocardiogram 
Please refer to section 5.2.4 for the detailed technical procedure. 
 Biobank Samples 
Biobank samples will be taken at the randomization visit (V0) before treatment initiation and 
at the end-of-treatment visit (V3). The Biobank assessments to be performed are listed in the 
following table (see Table 9). Based on scientific knowledge at the end of the study, this list might 
be updated to perform the most appropriate tests in the scope of NASH. 
Table 9 : Biobank tests 
Domain 
Goal 
Biomarker name 
Screen 
V0 
V1 
V2 
V3 
V4 
Inflammation 
Efficacy 
IL-13 
- 
 
- 
- 
 
- 
Efficacy 
IL-17A 
- 
 
- 
- 
 
- 
Efficacy 
IL-6 
 
 
 
 
 
 
Efficacy 
IL-1b 
- 
 
- 
- 
 
- 
Efficacy 
TNF-a 
- 
 
- 
- 
 
- 
Efficacy 
INFg 
- 
 
- 
- 
 
- 
Lipids 
Efficacy 
APO B 
- 
 
- 
- 
 
- 
Efficacy 
APO C3 
- 
 
- 
- 
 
- 
Efficacy 
cytokeratin M30 
- 
 
- 
- 
 
- 
Efficacy 
cytokeratin M65 
- 
 
- 
- 
 
- 
Efficacy 
liver iron content 
- 
 
- 
- 
 
- 
Efficacy 
MMP2 
- 
 
- 
- 
 
- 
Efficacy 
MMP9 
- 
 
- 
- 
 
- 
Fibrosis 
Efficacy 
Pro-C3 
- 
 
- 
- 
 
- 
Genotype 
Other 
PNPLA3 
- 
 
- 
- 
- 
- 
Genotype 
Other 
TM6FS2 
- 
 
- 
- 
- 
- 
 
o Biobank 
Biobank means that the blood and urine samples will be stored and analyzed only at the end of 
the study according to the efficacy results of the study and the need of further investigations to 
improve the knowledge of the mechanisms of action of lanifibranor. 
All blood and urine samples will be destroyed at the end of the scheduled storage period (1 year 
after the end of the study), when all analyses will be completed. 


 
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DNA sample will be stored up to 1 year after the end of the study for genetic analysis only related 
to the NASH Condition. 
o Genotype: 
Genetic polymorphism of PNPLA3 and TM6FS2 could be associated to progression from 
NAFLD to NASH and to liver fibrosis. Genotyping will therefore be performed to assess if variants 
strongly associated with NAFLD progression may confound treatment effect as well as to 
characterise the population that is included in this trial. 
DNA sample will be stored up to 1 year after the end of the study for genetic analysis only related 
to NASH. 
6.4 
Data Safety Monitoring Committee 
 Mission 
The DSMB will be responsible for safeguarding the interests of trial participants, assessing 
safety of the interventions during the trial. 
The DSMB will review the protocol and other clinical trial material to ensure that the study will 
provide useful information regarding the safety of lanifibranor in NASH and that it fulfills ethical 
requirements. 
The DSMB will provide recommendations about continuing or stopping the trial. 
The DSMB will be advisory to the steering committee. 
 Membership 
The DSMB is an independent multidisciplinary group consisting in clinicians and a 
biostatistician that, collectively, has experience with the conduct of randomized clinical trials. 
The DSMB membership will be restricted to individuals free of apparent significant conflict of 
interest. The source of these conflicts can be financial, scientific or regulatory in nature. Thus 
neither study Investigators nor individuals employed by the Sponsor, nor individuals who might 
have regulatory responsibilities for the trial product, can be members of the DSMB. 
 Safety monitoring 
The DSMB will be provided in a semi-unblinded way (treatment A, B, C), with ECG parameters 
(heart rate, QT, QTc Bazett and Fridericia, delta QTc Bazett and Fridericia, PR interval, ECG 
interpretation) and main laboratory assessments. In addition, they will be provided with a listing 
of all AE/SAEs. The DSMB may request a break of the blind, and SUSAR will be provided 
unblinded. 
The frequency of the DSMB and the criteria for ad-hoc meeting will be specified in the DSMB 
charter. 
 Organization 
The first meeting of the DSMB will be an organizational meeting. It will be held during the 
final stage of protocol development, to provide advisory review of the scientific and ethical issues 
relating to the study design and conduct, to discuss the standard operating procedures for the role 
and functioning of the DSMB, and to discuss the format of closed reports that will be used to 
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The organizational meeting will be attended by the DSMB, and by representatives of the 
Sponsor, the principal Investigator, and the CRO. The DSMB will be provided with draft of the 
protocol, the current version of the case report form (eCRF screens) and the initial draft of the 
closed report. 
The statistical analysis for the DSMB will be performed by an independent statistical team of 
the Keyrus Biopharma. This team will not be co-localised with the team of Keyrus Biopharma 
involved the monitoring/data management and project-management activities.The formal analysis 
meetings will be held to review data every 50 patients for the duration of the trial. 
 Procedures to ensure confidentiality and proper communication 
To enhance the integrity and credibility of the trial, procedures will be implemented to ensure 
that the DSMB has sole access to evolving information from the clinical trial regarding safety data 
aggregated by treatment arm in a semi-unblinded way, with a possibility of requesting a break of 
the blind. 
Confidential reports for the DSMB will be prepared in an automated way, based on electronic 
data capture and consolidation of ECG, laboratory data and SAE/SUSAR reports. 
The Chair of the DSMB will only communicate to the Trial Steering Committee (TSC) the 
recommendation to continue or stop the trial. Should there be a need to discuss any other matter 
the chair of the DSMB will convene a formal meeting with the TSC with a jointly agreed agenda. 
The trial steering committee will include a representative of each country involved in the study. 
 Minutes of the DSMB meetings 
The DSMB will prepare closed minutes of their meeting. The reports will be signed by all three 
members and originals kept by the chair until completion and archiving of the study. 
 Recommendations to the steering committee 
At each meeting of the DSMB during the conduct of the trial, the DSMB will make a 
recommendation to the TSC to continue or terminate the trial. This recommendation will be based 
on safety considerations and will be guided by the statistical monitoring guidelines defined in this 
section. 
7. Pharmacokinetic Assessments 
Pharmacokinetic sampling will be completed as described as indicated below. 
7.1 
IMP Concentration Measurements 
 Plasma Concentration 
Two pharmacokinetic blood samples (3 ml) will be drawn during the whole study, in the 
morning just before the drug intake of that day (trough level) 
 At V1 (week 4), first interim visit, 
 At V3 (week 24), end-of-treatment visit. 
The patient will be instructed to take his daily treatment after the samples taken. 
The exact times of the last drug intake and the sampling need to be noted in the eCRF. 
 Handling and Shipment of Samples 
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The whole blood samples (3 mL) for determination of lanifibranor will be collected by venous 
puncture or indwelling venous catheter into polypropylene tubes containing lithium heparin (Li-
Heparin). 
Samples will be immediately placed on ice water and subsequently (within 30 minutes of 
collection) centrifuged at 1760 g and at temperatures between +3°C to +5°C (if possible) otherwise 
at ambient temperature and for 10 minutes.  
For each 3 mL blood sample, two aliquots of exactly 0.5 mL plasma will be rapidly transferred 
into a screw-capped and stoppered (airtight) polypropylene tube containing 20 µL of 
orthophosphoric acid H3PO4 2.5 mol/L in order to stabilize the lanifibranor metabolites in plasma.  
The plasma samples will be homogenized by hand or with a vortex system and immediately 
stored at -80°C (if possible), otherwise at -20°C. The samples will be collected by DHL within 48 
hours and shipped on dry ice to CL. 
7.2 
Non-Compartimental Pharmacokinetic analysis 
Descriptive statistic of trough levels of lanifibranor will be presented. Individual plasma trough 
concentration of lanifibranor will be presented in listings. For V1 and V2 individual data of trough 
lanifibranor plasma concentration will be tabulated with descriptive statistics such as number of 
valid samples (n), mean, geometric mean, median, SD, minimum, maximum and coefficient of 
variation. Summary statistics will also be presented separately by gender 
8. Data Quality Assurance 
8.1 
Monitoring 
During study conduct, INVENTIVA or its representative will conduct periodic monitoring 
visits. During monitoring visits, the monitors will verify the adherence to the protocol, the 
maintenance of all study-related records and the accuracy and completeness of all eCRF entries 
compared with source data in order to ensure that: 
 Data are authentic, accurate, and complete. 
 Safety and rights of subjects are being protected. 
 Study is conducted in accordance with the currently approved protocol, ICH-GCP and 
all applicable regulatory requirements  
Any discrepancies identified must be resolved. The monitors will review source documents to 
confirm that the data recorded on eCRF is accurate. The Investigator and institution will allow 
INVENTIVA or its representative monitors and appropriate regulatory authorities’ direct access 
to source documents to perform the verification. 
The study sites may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by INVENTIVA, or 
companies working with or on behalf of INVENTIVA, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
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8.2 
Data recording 
Electronic Data Capture (EDC) will be used for this study, meaning that all data will be entered 
on an eCRF at the investigational site. This eCRF will be specifically designed for the study and 
developed by the Data Management Department of Keyrus Biopharma using Marvin®, a validated 
Electronic Records/Electronic Signature-compliant (21 CFR Part 11) application provided by the 
clinical company. 
In this clinical trial, only anonymized data will be recorded based on the clinical data collected. 
The anonymized data of medical information includes the results of the trials tests and will be 
communicated to the Sponsor or its representative.  
Only members of the research team, who also form part of the patient's direct clinical care team, 
at the participating sites will have access to patient records as part of their medical care and will 
use these records to screen for potentially eligible patients. Patients who consent to enter the trial 
are informed that staff from the research team, the Sponsor (and its representatives), relevant 
regulatory authorities and ethical committees may require access to their full medical records for 
monitoring and auditing purposes. 
After the end of the study (validation of the final report), the data will be totally anonymized 
and will be stored on a dedicated and secured slot on an Inventiva’s server. Only authorized 
Inventiva employees or its representative will have access to the data. 
8.3 
Data management 
 Responsibilities 
The KBP Monitors and/or Data Managers will provide all tools, instructions, and training 
necessary to complete the eCRF, and each user will be issued a unique username and password.  
The Data Management of KBP will be responsible for data processing, in accordance with the 
CRO data management procedures.  
The Investigators will have to verify that all data entries in the eCRF are accurate and correct. 
If some assessments are not done, or if certain information is not available, not applicable, or 
unknown, the Investigators will have to indicate this in the eCRF. The Investigators will be 
required to electronically sign off the clinical data.  
The Monitors will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies. 
All entries, corrections, and alterations will be made by the Investigator or his/her delegate. The 
Monitors cannot enter data in the eCRFs. 
 Data collection and validation 
All clinical data will be entered in the eCRF at the investigational sites. For each patient of a 
given site (screen failure and enrolled), an eCRF must be completed in English, by the Investigator 
or designee, and signed by the Investigator. 
A unique subject code will identify the subjects on the eCRF.  
Once clinical data of the eCRF have been submitted to the central server, corrections to the data 
fields will be audit trailed, meaning that the reason for change and the name of the person who 
performed the change, together with time and date, will be logged. Roles and rights of the site 
personnel responsible for entering the clinical data into the eCRF will be determined in advance 
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Automatic checks and listings will be designed and performed according to the data validation 
plan, developed by Keyrus Biopharma Data Managers and approved by Inventiva. In case of 
missing values, out of range values, data inconsistencies or values that fail logical checks, queries 
will be edited in the EDC application. In addition, the Monitors and Data Manager(s) can raise 
manual queries in the EDC application. 
The appropriate investigational staff will answer automatic and manual queries. This will be 
audit-trailed by the EDC application, meaning that the name of the person who answered and the 
time and date stamp are captured. 
 Data coding 
AEs and Medical History (MH) will be coded using the last version of MedDRA terminology. 
Concomitant medications will be coded using WHO Drug 2016 Q1 (or a more recent version) 
terminology.  
The medical coding will be performed by Keyrus Biopharma coding specialist and reviewed by 
a Keyrus Biopharma physician before being submitted to Inventiva for approval. 
 Database lock 
Once validated, the database will be locked so that no more change will be possible on the 
frozen data.  
After database lock, the Principal Investigator will receive a CD-ROM of the patient data (eCRF 
data + audit trail) for archiving at the investigational site. 
 Database transfer 
Final validated data will be transferred in a secure way to Inventiva and the Biostatistical team 
in SAS format (SAS datasets format). 
8.4 
Independent Audit 
The Investigator will permit an independent audit by an auditor mandated by the Sponsor, after 
reasonable notice. An audit or a regulatory inspection is intended to determine if the study was 
conducted as per protocol (PP), GCP and applicable regulatory requirements, if the rights and well-
being of the patients were protected, and if the data relevant for the evaluation of the IMP were 
captured, processed and reported in compliance with the planned arrangements. 
8.5 
Regulatory Inspection 
Regulatory authorities may perform an inspection of the study including several years after its 
completion. As for an audit, the Investigator will permit a direct access to all study documents, 
drug accountability records, source records and source data. If an inspection is announced, the 
Sponsor will be informed without delay. 
9. Statistical Methods 
9.1 
Efficacy Assessments 
Primary endpoint: The primary efficacy endpoint will be a binary variable (responder / non-
responder) based on the change from baseline to Week 24 of the SAF activity score. Responder is 
defined as a decrease from baseline to week 24 of at least 2 points of the SAF activity score 
combining hepatocellular inflammatory and ballooning without worsening of fibrosis. Any stage 
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least one of the two doses increases the percentage of responders compared to placebo?”. The main 
comparison of interest is therefore each of the two verum groups versus placebo. 
Secondary endpoints: The following changes from baseline to 24 weeks of treatment will be 
evaluated:  
 Percent of patients with resolution of NASH (Steatosis with or without mild 
inflammation and no worsening of fibrosis) from baseline to end of treatment (week 
24). 
 Percent of patients with a change in components of SAF score from baseline to end of 
treatment (week 24):  
- 
Steatosis: -1 point 
- 
Lobular inflammation: -1 point 
- 
Ballooning: -1 point 
 Percent of patients with at least 1-point improvement of fibrosis score on a 4-point scale 
(SAF) without worsening of NASH, defined as no increase for ballooning, 
inflammation, or steatosis, using the SAF scoring system, from baseline to end of 
treatment (week 24). 
 Change in fibrosis score on a 4-points scale (SAF) and modified Ishak: - one point from 
baseline to end of treatment (week 24).  
 Liver enzymes (ALT, AST, γGT) change from baseline to end of treatment (week 24). 
 Inflammatory markers (fibrinogen, hs-CRP, alpha2 macroglobulin and haptoglobin 
levels) change from baseline to end of treatment (week 24). 
 Glucose metabolism (fasting glucose and insulin, HOMA index and, in subjects with 
T2DM, HbA1c) change from baseline to end of treatment (week 24). 
 Main plasma lipids levels (TC, HDL-C, calculated LDL-C, TG and apoA1) change 
from baseline to end of treatment (week 24).  
 Adiponectin change from baseline to end of treatment (week 24). 
Exploratory endpoints:  
 Specific markers of inflammation, lipids, glucids, fibrosis, bone remodeling change 
from baseline to end of treatment (week 24). 
 Transient Elastography (TE) and Controlled Attenuation Parameter (CAP) change from 
baseline to end of treatment (week 24). 
 If deemed necessary: Immunohistochemistry: change in the semi quantitative score of 
ballooning and stellate cell activation from baseline to end of treatment (week 24).  
9.2 
Sample Size 
The expected rate of responders according to the retained definition was estimated to 10% for 
the placebo by a group of clinical expert. An excess rate of responders of 20% was accepted as 
clinically pertinent. It corresponds to a multiplication of chance of success (responders) of 3 and a 
NNT of 5. The sample size required to reach a power of at least 80% is 72 patients per group with 
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responders in the placebo group. For example, if the rate of responders is 15% instead of 10% then 
85 patients are required. If the true rate is lower than 10% then less patients may be sufficient. The 
sample size is therefore rounded in the conservative side of 75 patients per group. 
Based on the experience of previous clinical trials, it is estimated that 100 patients per group 
will need to be screened to randomize 75 patients after central reading of liver biopsy confirms the 
NASH diagnosis and activity. In case the end of study liver biopsy slides are not available or not 
interpretable in more than 5% of patients, an amendment will be submitted to increase sample size 
accordingly. 
9.3 
Randomization 
Patients will be randomized equally 1:1:1 to either dose of lanifibranor or placebo stratified on 
presence/absence of diabetes. Strata will be self-weighted i.e. patients meeting inclusion/exclusion 
criteria will be recruited as they come (no quota). 
The randomization list will be setup with blocs of size equal to 6. 
After identification with a login and a password, the randomization process will be provided 
through an Interactive Web Response System (IWRS) integrated to the eCRF. Once a set of 
medical carateristics are entered, the system lets you know immediately, which medication kit to 
use for this particular patient. 
9.4 
Protocol Deviations 
Protocol deviators will be identified and classified at the blind review. Only patients with major 
deviations will be discussed in the Clinical Study Report and excluded from the per protocol 
analysis. 
9.5 
Data sets Analyzed 
- 
Full analysis set (FAS)  
The full analysis set consists of all randomized patients who received at least one dose of the 
assigned treatment. In case of error in the assignment of treatment, the actual treatment will be 
used in the FAS instead of the treatment assigned in the randomization list.  
- 
Randomized set of patients 
The randomized set of patients consists of all randomized patients. In case of treatment error, 
the treatment assigned in the randomization list will prevail over the actual received treatment. 
- 
Set of evaluable patients 
The set of evaluable patients will consist of the FAS after exclusion of all patients without post-
randomization assessments. Concerning the primary endpoint, the absence of post randomization 
assessment will be considered a failure and the patient will therefore be evaluable if the withdrawal 
is possibly due to lack of efficacy or safety concern. The same rule will be applied for other binary 
efficacy variables. 
- 
Per protocol set of patients 
This set is composed of all patients free from major protocol deviation which can bias the 
estimate of the treatment effect. Patients with major deviations will be listed during the blind 
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- 
Safety set of patients 
The safety set of patients consists of the FAS who will have taken at least one dose of treatment 
and who have at least one post-baseline assessment of safety, regardless any protocol deviations. 
In case of treatment error, the actual treatment will be used.  
Safety analyses will be conducted on the safety population which includes all the exposed 
population, i.e. all patients who will have taken at least one dose of IVA337 and who have at least 
one post-baseline assessment of safety, regardless any protocol deviations. 
9.6 
Demographic and Other Baseline Characteristics 
 Patient Demographic Characteristics, Medical History and Diagnoses 
Safety characteristics, including demography, medical history, entrance criteria deviations will 
be summarized using the descriptive statistics (N, mean, standard deviation, minimum and 
maximum for quantitative values and counts and percents for qualitative variables). 
 Previous Medications 
The use of prior medications will be summarized. 
9.7 
Safety Analysis 
The review of safety and tolerance will be performed on the safety population. The safety 
analysis will be based on the reported AEs and other safety information. The effect of the 
demographic differences (gender, age, etc.) and risk factors of clinical relevance will be explored. 
 Extent of Exposure 
The extent of exposure will be summarized descriptively (N, mean, median, standard deviation 
and range) using treatment exposure duration. Treatment exposure duration (in days) is defined as: 
(Date of last dose of study product - First intake of study product date). The distribution and 
cumulative distribution of patients by treatment exposure duration will be summarized for the 
safety population. 
 Adverse Events 
Each AE will be coded to a "preferred term" and associated "system-organ class" according to 
an established and validated adverse reaction dictionary (MedDRA). The AE endpoints are number 
of patients experiencing: - at least one event - an event under each recorded preferred term, - an 
event under each recorded system-organ class. These endpoints apply to all AEs, regardless of 
relationship of the event to lanifibranor. 
- 
Definitions: 
Adverse events will be coded according to Medical Dictionary for Regulatory Affairs 
(MedDRA) and coded as treatment emergent (TEAE) / non-treatment emergent (non-TEAE) 
according to the following definitions. TEAEs are defined as events occurring on or after the day 
of first dose intake of study product and up to follow up visit. Additionally, events present before 
the first dose of study product, but worsening under treatment are considered as TEAEs. Although 
every effort will be made to establish the onset date and time, events with missing onset date will 
be considered as TEAEs. An AE that will not qualify as a TEAE will be considered as a Non-
TEAE. Non-TEAES will be summarized separately from TEAES, and will be presented in the 
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- 
Treatment Emergent Adverse Events 
A given TEAE will be counted once only per patient. The percentages will be calculated in 
relation to the population exposed (i.e., safety population). All TEAES will be analyzed, 
irrespective of their causal relationship with lanifibranor. Recapitulative tables will be provided, 
showing the following: 
 count of exposed patients, 
 count and percentage of patients with at least one TEAE, 
 count and percentage of each TEAE: TEAEs will be sorted by decreasing order of organ 
system frequency then by decreasing order of preferred term frequency, 
 count and percentage of each TEAE, not taking into account organ system. 
In addition, TEAEs will be described according to their time to onset with same categories as 
for duration of exposure, their maximal intensity and their relationship to lanifibranor, gender and 
age of patient, time from first intake, outcome, seriousness criteria, corrective treatment, duration, 
treatment received and action taken. Patient data listings will be provided for all AEs, TEAEs, AEs 
leading to study discontinuations and SAEs. 
Deaths and Serious Adverse Events Incidence of SAEs (irrespective of their emergence 
classification and relationship to lanifibranor) and deaths will be listed and summarized. 
- 
Adverse Events leading to treatment discontinuation  
Adverse event leading to discontinuation of the study will be tabulated, irrespective of their 
emergence classification and irrespective of their relationship to lanifibranor. 
 Other Observations Related to Safety 
- 
Laboratory tests 
The analysis will include patients exposed to study medication who have at least one laboratory 
test performed after the first study product intake and, when required by the definition of the 
abnormality, with an available baseline value and available normal ranges. For these descriptions, 
the baseline value will be the latest available measure before the first study product dose intake. 
International units will be used in all listings, tables and graphs. Results and changes from baseline 
of laboratory parameters will be summarized by mean, standard deviation, median, minimum and 
maximum at each time point and for the final on-treatment visit. Unscheduled and/or repeated 
results will only be listed and not summarized. 
Shift tables and other tabular and graphical methods will be used to present the results for tests 
of interest. Listings will be provided with flags indicating clinically significant out-of-range values, 
clinically non-significant out-of-range values. 
In addition, out-of-range values will be assessed by the investigator as clinically significant or 
not clinically significant. Abnormal laboratory tests assessed by the investigator as clinically 
significant will be reported as an AE. 
- 
Vital signs and ECG 
Descriptive statistics by time point will be computed on actual values and changes from baseline 
for vital signs and ECG data. The baseline value is defined as the last measure before study product 
intake. ECG parameters collected are heart rate, PR interval, QRS interval, QT, QTcB (Bazett) 
intervals. Descriptive statistics (means, standard deviations, and ranges) and changes from baseline 


 
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values for all visits will be provided. The summaries will include patients who have at least one 
measurement performed after the first study product intake. Results and changes from baseline of 
the following vital sign parameters will be summarized by mean, standard deviation, median, 
minimum and maximum at each time point and the final on-treatment visit: 
 Heart rate: supine, 
 Systolic blood pressure: supine, 
 Diastolic blood pressure: supine, 
 Weight. 
Shift tables and other tabular and graphical methods (plots of mean over time) may be used to 
present the results for parameters of interest. 
Confirmatory inferential analysis may be done for parameters of interest. Listings will be 
provided with flags indicating clinically significant out-of-range values, clinically non-significant 
out-of-range values. 
Any ECG modification or change in vital sign compared to screening, considered as clinically 
significant by the Investigator, will be reported as an AE. 
- 
Physical examination 
For physical examination anomalies will be listed and frequencies tables will be computed. 
When considered clinically relevant by the Investigator, any new finding of the physical 
examination, compared to the screening visit, will be reported as an AE. 
 Efficacy Analyses 
Primary efficacy analysis  
The primary population will be the intent to treat FAS population composed of all randomized 
subject who received at least one dose.  
The primary efficacy endpoint will be a binary variable (responder / non responder) based on 
the change from baseline to Week 24 of the SAF activity score. Responder is defined as a decrease 
from baseline to week 24 of at least 2 points of the SAF activity score combining hepatocellular 
inflammatory and ballooning without worsening of fibrosis. 
The primary tests of hypotheses will be the Cochran Mantel Haenszel test stratified on diabetes 
comparing the high dose to placebo and the low dose to placebo. The ascending Hochberg 
procedure will be used for adjusting the type one error which is globally set at 0.05 two-
sided. The primary measure of the effect size will be the CMH odds ratio with an adjustment 
for diabetes. Because the odds ratio is not easy to interpret when the rate of responders in the 
placebo group is not very small the odds ratio (OR) and its confidence interval will be 
converted in Risk Ratio (RR) using the following formula RR = (P1/P0) = OR/[(1−P0) + 
(P0×OR)] (75). The log-binomial model will preferentially be used in the absence of 
convergence or estimability issue for estimating the effect size with RR. 
The primary rule for handling the missing data is to consider non-responders all patients who are 
not confirmed responders.  
The primary handling of centers is to ignore in the primary analysis the center effect because 30+ 
centers should be involved in the study and the number of empty cells in the breakdown of 
the site by treatment by stratum table can be large (sparse contingency table).  


 
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The primary handling of multiplicity of testing will be done through the Hochberg procedure.  
The primary handling of heterogeneity of result across strata will be performed through the 
Breslow-Day test. If the homogeneity hypothesis is rejected, then the estimate of the 
difference in percentage points between each dose and placebo along with the 95% C.I. will 
be calculated within each stratum. If the interaction between stratum and treatment (Breslow 
Day test) is significant it means that the treatment effect has not the same magnitude in 
diabetic and non-diabetic patients. In the absence of qualitative interaction there will be no 
further adjustment of the type one error for multiplicity of testing. 
The generalizability of the treatment effect across geographical area will be tested and the 
statistical strategy will be defined in the SAP once the sample size will be known by stratum and 
country and before the break of the randomization code. 
There is no planned interim analysis for success. However, the DSMB may decide to perform 
some futility analyses in particular in case of safety concerns.  
A series of sensitivity analyses will be performed to assess the robustness of results such as the 
use of a stratified test (country as a stratification factor), the use of other sets of patients (PP set, 
Evaluable set, Randomized set, completer set). In case of missing assessment at W24, the patient 
will be considered a non-responder. A responder is consequently a confirmed responder.  
Secondary efficacy analyses: 
 NASH improver rates in each dose will be compared to placebo 
using the Cochran Mantel Haenszel test stratified on diabetes. 
 Percent of patients with resolution of NASH in each dose will be 
compared to placebo using the Cochran Mantel Haenszel test 
stratified on diabetes. 
 Percent of patients with a change in components of SAF score in 
each dose will be compared to placebo using the Cochran Mantel 
Haenszel test stratified on diabetes. 
 Percent of patients with at least 1-point improvement of fibrosis 
without worsening of NASH in each dose will be compared to 
placebo using the Cochran Mantel Haenszel test stratified on 
diabetes. 
Planned exploratory analyses: 
 Inflammatory markers (fibrinogen, hs-CRP, alpha2 macroglobulin 
and haptoglobin levels) change from baseline to end of treatment 
(week 24) will be compared using GLM with the diabetes and dose 
as covariates. A mixed model for repeated measures will also be 
used to compare the time course of the response of each treatment 
group. 
 Transient Elastography and Controlled Attenuation Parameter 
change from baseline to end of treatment (week 24) will only be 
described.  
 Glucose metabolism (fasting glucose and insulin, HOMA index and, 
in subjects with T2DM, HbA1c) change from baseline to end of 
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and dose as covariates. A mixed model for repeated measures will 
also be used to compare the time course of the response of each 
treatment group. 
 Main plasma lipids levels (TC, HDL-C, calculated LDL-C, TG and 
apoA1) change from baseline to end of treatment (week 24) will be 
compared using GLM with the diabetes and dose as covariates. A 
mixed model for repeated measures will also be used to compare the 
time course of the response of each treatment group.  
 Adiponectin change from baseline to end of treatment (week 24). 
Comparison tests and estimates of the difference in the change from 
baseline will be performed using GLM with the diabetes and dose 
as covariates. A mixed model for repeated measures will also be 
used to compare the time course of the response of each treatment 
group. 
 Immunohistochemistry if deemed necessary: change in the semi-
quantitative score of ballooning and stellate cell activation from 
baseline to end of treatment (week 24) will be compared using a Van 
Elteren rank test stratified on diabetes.  
The SAP will provide more details on the presented analyses as well as on other exploratory 
criteria such as quality of life assessment.  
All secondary efficacy analyses will be performed using a mixed model for repeated measures 
or an ANCOVA model if only one post-randomization measure is available. CMH test stratified 
on diabetes will be used for qualitative variables.  
Exploratory analyses on the biomarkers measurements and other evaluations will be proposed 
and described in the statistical analysis plan. 
The final version of the Statistical Analysis Plan will be issued before freezing of the database 
the break of the randomization code. Any clarification brought in the SAP concerning handling of 
data and statistical analyses will prevail over any other interpretations of the protocol unless it is 
the source of major inconsistencies. 
10. Patient Withdrawal & Replacement 
10.1 Patient Withdrawal 
Participation in the study is strictly voluntary. The patients have the right to withdraw from the 
study at any time for any reason, without the need to justify. The Investigator also has the right to 
withdraw patients in case of safety concerns, protocol deviations or administrative reasons. Since 
an excessive rate of withdrawals can render the study uninterpretable, the unnecessary withdrawal 
of patients must be avoided.  
Reasons of withdrawal include, but are not limited, to the following: 
 Patient decision 
 Lost to follow-up, death 


 
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 Any AE, laboratory abnormality or illness which, in the opinion of the Investigator, 
indicates that continued treatment with study therapy and participation in the trial is not in 
the best interest of the subject. 
 Major protocol deviation: e.g. lack of compliance with scheduled visits, non-compliance 
with study treatment, treatment with prohibited medication during the study (see 22) 
 Any deterioration in cardiac status 
 ALT or AST > 8 x ULN; or if ALT or AST > 5xULN for more than 2 weeks; or if ALT or 
AST > 3xULN and bili (total) > 2xULN (or INR>1.5); or ALT or AST > 3xULN and 
symptoms (Right Upper Quadrant pain, nausea, …) 
 Investigator’s decision for any other reason 
If a patient discontinues the study, the Investigator will make reasonable efforts to obtain the 
reason and to perform all protocol-defined end of study assessments as soon as possible. The 
reason and circumstances for premature discontinuation (e.g. consent withdrawal, AE, lost to 
follow up, etc.), and the date of withdrawal must be documented in the eCRF. If a patient 
discontinues the study for safety reasons, the outcome must be known. 
In the case of withdrawal due to pregnancy (see paragraph 6.2.1), the patient will be followed 
until outcome, i.e. at least on a quarterly basis for follow-up evaluation of the pregnancy, foetus, 
delivery and new born.In the case of withdrawal due to an AE the patient will be followed until 
resolution of the AE, or until in the opinion of the Investigator the event has stabilized, and the 
patient is referred to their primary physician for appropriate management of the ongoing event. 
Reasonable efforts will be made to contact a patient who fails to attend any follow-up 
appointments, in order to ensure that he/she is in satisfactory health. 
Health data and biological samples collected during the whole participation of the patient will 
be analysed at the end of the study, and the biological samples stored up to one year after the 
completion of the study and destroyed. 
10.2 Unblinding Process 
 Unblinding for emergency 
The code breaks will be available 24 hours a day and 7 days a week using an Interactive Web 
Response System (IWRS) implemented via the eCRF.  
The IWRS will require an access code/password/PIN and are only available to staff members 
named on the delegation log for the trial recorded in the Trial Master file of each site.  
The Investigators and delegated members with unblinding responsibilities are responsible for 
testing their username and password prior to the treatment of subjects to ensure unblinding is 
possible, or for ensuring appropriately trained staff members are available to action code breaks 
when required for medical emergencies which may be required out of normal working hours. 
Sealed envelopes containing the code-break information will be provided to the 
Pharmacovigilance and safety Institution (Stragen, see 2.3). 
Details of any emergency unblinding shall be documented fully in the Sponsor file, Investigator 
TMF and Pharmacy and Site File(s). This includes, but may not be limited to:  
1) Date,  
2) Subject details,  


 
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3) Reason for unblinding,  
4) The results,  
5) Name and role of the individual requesting the unblinding,  
6) Name and role of the individual carrying out the unblinding. 
If the Clinical Trials Pharmacy or an individual as named on the Delegation Log has performed 
the procedure, they will inform the Sponsor the trial identifier, subject number and name and title 
of the person making the request, but NOT the result. The details shall be included in the statistical 
report.  
 Unblinding for DSMB 
Informations will provided to the DSMB unblinded, if requested. 
To that effect, a named statistician not involved with the final data analysis or with the study, 
shall receive the relevant codes. A record shall be kept in the TMF of the name of the statistician, 
the date they were supplied the relevant code breaks and the location of the results. The unblinded 
data and the results supplied to the DSMB shall not be accessible by the Investigators or trial staff. 
 Unblinding at end of trial  
The Statistical Analysis Plan shall be provided in the protocol or be finalized prior to the release 
of the randomization codes. Changes to the statistical analysis plan shall be version controlled. A 
record shall be kept in the Investigator TMF to confirm when the randomization code was 
requested and when provided.  
11. Training & Information 
11.1 Training 
All persons involved in the study will be trained in an effort to standardize relevant methods, 
ratings and data capture and to prevent deviations. 
11.2 Information of the Investigator 
The Investigator will receive all the relevant information for a safe use of the IMP as the study 
proceeds. 
12. Records & Data 
12.1 Source Records & Data 
Source data are all the information in original records and certified copies of original records 
of clinical findings, observations, or other activities in the study, which are necessary for the 
reconstruction and evaluation of the study. The Investigator will permit study-related monitoring, 
audits, IEC reviews and regulatory inspections, with a direct access to all the required source 
records. For each patient enrolled, the Investigator will note in the source records that the patient 
participates in this study, and will record the following information: concomitant therapies, 
clinically significant adverse events and a statement at patient end of participation. 


 
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12.2 Case Report Forms 
Electronic Case Report Form (eCRF) will be provided by the CRO institution. The Investigator 
is responsible for maintaining adequate and accurate data into the eCRF which has been designed 
to record all observations and other data pertinent to the clinical investigation.  
All data requested on the eCRF must be filled out completely by the Investigator or the 
Investigator team. All data captured for the study is planned to be electronic. The eCRF should be 
reviewed and electronically approved by the Investigator.  
All missing data must be explained. If any entry error has been made, to correct such an error, 
enter the correct data above it. All such changes will be must electronically signed with the reason 
for the correction if necessary, by an authorized (Investigator/co-worker) person.  
eCRF and all other source data must be easily accessible for review during the programmed 
monitoring visits. Once the clinical monitor has verified the contents of the completed eCRF 
against the source data, the system will be verified electronically by the clinical monitor for those 
pages. Queries may be raised if the data are unclear or contradictory, which must be addressed by 
the Investigator. 
Patients are not to be identified in the eCRF by name or initials and birth date. Appropriate 
coded identification, e.g. patient number in combination with year of birth must be used. 
13. Confidentiality 
13.1 Confidentiality of Patient Data 
The Investigator will ensure that the confidentiality of the patients’ data is preserved. On eCRFs 
or any other documents for the Sponsor, the patients will not be identified by their names, but by 
their initials and numbers in the study. Documents not for transmission to the Sponsor, e.g. the 
confidential patient identification list and the signed informed consent forms will be maintained 
by the Investigator in strict confidence. 
13.2 Confidentiality of Sponsor Data 
Any information on the IMP, this study and its results is confidential information. The 
Investigator, study site personnel and IEC members will not use, publish, or otherwise disclose 
any confidential information without the prior written authorization from the Sponsor. Any data, 
results, inventions and patents that may arise from this study will be the exclusive property of the 
Sponsor. 
14. Reporting & Publication 
14.1 Study Report 
All the relevant data and information will be reported in a study report prepared by CRO 
(KEYRUS BIOPHARMA, section 2.2) and submitted to the Sponsor and the Investigators for 
review comments and signature. The final study report will be used for the further development of 
the IMP and regulatory submissions. 


 
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14.2 Disclosure of Data and Publications 
No information provided by INVENTIVA S.A. to the Investigators for the purposes of 
performing the study, will be published, or passed on to a third party, without prior written approval 
by INVENTIVA. 
The Investigators will have full access to all of the study data and will take complete 
responsibility for the integrity of the data and the relevance of the data analysis and reporting. 
After regulatory clearance, the study will be registered by the Sponsor in the ClinTrials.gov 
database. The Principal Investigator or anyone else working on the study will submit all proposed 
publications, papers, abstracts or other written materials or an outline of any proposed oral 
presentation related to the study to INVENTIVA S.A. at least 1 month prior to (i) submission of 
such written materials for publication, or (ii) any proposed oral disclosure to a third party. 
INVENTIVA S.A. shall have the right to comment on such written material/outline and to take 
any necessary action to protect its intellectual property; the Principal Investigator, in determining 
the final form of disclosure, shall consider such comments in good faith. Notwithstanding any of 
the above, the Principal Investigator or anyone else working on the Study may not include any 
confidential information unrelated to the study in any such publication or disclosure. 
The Investigator will provide INVENTIVA S.A. with complete test results and all data derived 
from the study in accordance with the protocol. 
Only INVENTIVA S.A. and its authorized contractor may make information obtained during 
the study available to regulatory agencies, except as required by regulation. 
15. Record Keeping 
15.1 Study Site Records 
The Investigator is responsible for maintaining all the records which enable the conduct of the 
study at the study site to be fully understood. The study documentation and source records will be 
archived for the maximum period of time permitted by local requirements. The Investigator will 
complete the confidential patient identification list which provides the sole link between source 
records and anonymous eCRF data. The Investigator will retain this confidential list and the signed 
consent forms for at least fifteen years after the completion or discontinuation of the study. No 
study site records may be destroyed without prior written agreement between the investigator and 
the Sponsor. If the Investigator intends to assign the study documents to another party, or to move 
them to another location, the Sponsor must be notified. 
15.2 Study Master File 
The Sponsor will archive the study master file in accordance with GCP and applicable 
regulatory requirements. 


 
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2009 Mar;49(3):1017–44.  
69.  EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease 
severity and prognosis. J Hepatol. 2015 Jul;63(1):237–64.  
70.  de Lédinghen V, Hiriart J-B, Vergniol J, Merrouche W, Bedossa P, Paradis V. Controlled 
Attenuation Parameter (CAP) with the XL Probe of the Fibroscan®: A Comparative Study 
with the M Probe and Liver Biopsy. Dig Dis Sci. 2017 Sep;62(9):2569–77.  
71.  Sasso M, Beaugrand M, de Ledinghen V, Douvin C, Marcellin P, Poupon R, et al. Controlled 
Attenuation Parameter (CAP): A Novel VCTETM Guided Ultrasonic Attenuation 
Measurement for the Evaluation of Hepatic Steatosis: Preliminary Study and Validation in a 
Cohort of Patients with Chronic Liver Disease from Various Causes. Ultrasound Med Biol. 
2010 Nov;36(11):1825–35.  
72.  Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography 
(FibroScan ® ) with controlled attenuation parameter in the assessment of liver steatosis and 


 
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fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand? World J 
Gastroenterol. 2016;22(32):7236.  
73.  Karlas T, Petroff D, Sasso M, Fan J-G, Mi Y-Q, de Lédinghen V, et al. Individual patient 
data meta-analysis of controlled attenuation parameter (CAP) technology for assessing 
steatosis. J Hepatol. 2017 May;66(5):1022–30.  
74.  Pavlides M, Banerjee R, Tunnicliffe EM, Kelly C, Collier J, Wang LM, et al. Multiparametric 
magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. 
Liver Int. 2017 Jul;37(7):1065–73.  
75.  Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort 
studies of common outcomes. JAMA. 1998 Nov 18;280(19):1690–1.  
76.  Kleiner DE, Brunt EM, Natta MV, Behling C, Contos MJ, Cummings OW, et al. Design and 
validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 
2005 Jun;41(6):1313–1321.  
 
 


 
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APPENDICES 
APPENDIX A: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ...............................81 
APPENDIX B: METHODS AND NORMAL VALUES FOR VITAL SIGNS, WAIST AND ECG ..................89 
APPENDIX C: LIVER BIOPSY AND HISTOLOGY METHODS ............................................................92 
APPENDIX D : SF-36 QUESTIONNARY ........................................................................................97 
APPENDIX E : THE FLINDERS FATIGUE SCALE (FFS) ...............................................................102 


 
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APPENDIX A: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 


 
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APPENDIX B: METHODS AND NORMAL VALUES FOR VITAL SIGNS, WAIST AND 
ECG 
1. VITAL SIGNS 
Systolic and diastolic blood pressure, and heart rate measures are performed by a 
sphygmomanometer, using the oscillometric method lying after 10 minutes rest (DBP: 50≥N≥90 
mm Hg; SBP: 100≥N≥140 mm Hg; HR: 50≤N≤100 bpm). 
2. WAIST MEASUREMENT 
The Waist measurement must be done at midway between the top of the hip bone and the bottom 
of the ribs during a normal breathe out 
3. ELECTROCARDIOGRAM RECORDINGS 
a. ECG expected format 
CardiaBase - Banook Group minimum recommendations on the paper quality are following 
ones:  
 a 12-lead ECG recording including : 
 ECG print out using an A4 format with all ECG leads displayed on a single page 
There are many suitable ECG formats, and the two preferred ones are 6x2 and 4x3.  
With the 6x2 format, the six standard leads are shown on the left part of the A4 page (lead I 
down to lead aVF) and the six precordial leads on the right part (Lead V1 down to lead V6).  
 
 
 With the 4x3 format, the order sequence is I/II/III then aVR/aVL/aVF followed by 


 
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V1/V2/V3 and V4/V5/V6. 
 
 
 
 Regardless of the ECG format, it should include a “rhythm lead” with all individual cardiac 
beats, typically lead II to allow rhythm statements 
 The tracings should clearly show lead ID, the calibration pulse ,the recording speed and 
finally the gridlines should be clearly visible 
 A rhythm strip of 6 to 10 seconds, using the multi-channel (12 leads simultaneously) 
 
Note: should the machine you have on-site not be able to print in A4 format, CardiaBase - 
Banook Group is able to accommodate other formats but the A4 format is the preferred one. 
b. ECG Code 
For each patient, one ECG per visit is performed. 
3 visits are expected for each patient:  
 V-1, which is the Baseline ECG  
 V1 which is the WEEK4 ECG,  
 V3 which is the WEEK24 ECG. 
c. Documents provided to Sites by CardiaBase - Banook Group  
Electronic version (pdf format) of the following documents will be sent: 


 
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NATIVE IVA337 
Site |__|__|__|__| 
PatientNumber:|__|__|__|__||__|__|__| 
Visit: |__|__|__| 
ECG Date : |__|__|/|__|__|/|__|__|__|__| 
 User manual for sites 
 Transmission form 
Other documents, as UPS Airway bills, pre-identified envelopes, black labels and labels 
customized for the study to identify each ECG print-out, will be sent by courier to each site. 
d. Preparation of ECGs for shipment 
Review of each ECG will be performed in timeframe of the study.  
This ECG review will be performed upon receipt of each ECG after query resolution. 
 
Printouts of ECGs with the corresponding completed transmission form have to be sent to 
CardiaBase - Banook Group by the site just after the recording.  
 
Sites should record ECG in double print-out (i.e. 2 originals, NO PHOTOCOPIES) in order to 
keep one in patient’s medical file and to send the other one to CardiaBase - Banook Group. 
If the ECG device set-up does not allow to double-print the same ECG, and only in this case, 
the site will print the ECG, copy it. The copy will be kept on site and the original tracing will be 
sent to CardiaBase - Banook Group. 
 
The site will send a blinded print-out of each standard ECG with the corresponding transmission 
form duly completed. All handwritten information or automatic ECG analysis will be hidden with 
the black labels sent by CardiaBase - Banook Group.  
 
The paper speed and the ECG date should be kept visible. 
A label will be stuck on each ECG page to well identify the study, patient and ECG (visit and 
date) with paying attention to leave the leads available for analysis.  
 
 
 
 
 
 
 
 


 
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APPENDIX C: LIVER BIOPSY AND HISTOLOGY METHODS 
1. THE SAF SCORING SYSTEM 
The SAF assesses both and separately the grade of steatosis (S), the grade of activity (A), and 
the stage of fibrosis (F), the latter according to the NASH Clinical Research Network (CRN)(76). 
Steatosis is assessed by the percentage of hepatocytes containing large and medium-sized 
intracytoplasmic lipid droplets (but not foamy microvesicles), on a scale of 0 to 3 (S0: <5%; S1: 
5%-33%, S2: 34%-66%, S3:>67%). Ballooning of hepatocytes is graded from 0 to 2 (0: normal 
hepatocytes with cuboidal shape, sharp angles and pink eosinophilic cytoplasm; 1: presence of 
clusters of hepatocytes with a rounded shape and pale cytoplasm, usually reticulated where, 
although the shape is different, the size is similar to that of normal hepatocytes; 2, as for grade 1, 
but where there was also at least one enlarged ballooned hepatocyte (at least 2-fold size compared 
with that of normal cells within a cluster of hepatocytes with grade 1 ballooning). Lobular 
inflammation is defined as a focus of two or more inflammatory cells within the lobule organized 
either as microgranulomas or located within the sinusoids. Foci are counted at 20x magnification 
(grade 0: none; 1: < 2 foci per lobule; 2: >2 foci per lobule). The grade of activity (A from A0 to 
A4) is calculated by addition of grades of ballooning and lobular inflammation. Aspects of grading 
are illustrated Figure 5. 
 
Figure 5: Histological grading used in SAF score. 
Grading of steatosis.  
(A) Grade 1, lipid droplets in 30% of hepatocytes 
(H&E, x2.5). (B) Grade 2, steatosis in 60% of 
hepatocytes, (H&E, x2.5). (C) Grade 3: steatosis in 
>80% of hepatocytes (H&E, x2.5). Hepatocyte 
ballooning and clarification. (D) Ballooning grade 1: 
rounded hepatocyte with pale cytoplasm and size quite 
similar to that of normal hepatocytes (H&E, x20). (E) 
Ballooning grade 2: presence of enlarged hepatocyte at 
least 2-fold that of normal cells in a background of clear 
and rounded hepatocytes, arrow (H&E, x20). Lobular 
inflammation. (F) Lobular inflammation grade 1: two 
small foci of inflammatory cells, arrow (H&E, x20).(G) 
Lobular 
inflammation 
grade 
2: 
several 
large 
inflammatory foci (arrow) (H&E, x20). 
 
 
 
 


 
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2. LIST OF VARIABLES DERIVED FROM LIVER BIOPSY 
1. Biopsy length  ______ mm (to be completed) 
2. Tissue adequacy for evaluation 
Yes  
No  
3. Steatosis  
3a Grade (according to NASH CRN): 
Grade 0 
 
Grade 1 
 
Grade 2 
 
Grade 3 
 
 
3b Location: 
Zone 3 (central)  
 
Zone 1 (periportal)  
Azonal 
 
 
Panacinar  
 
4. Hepatocyte Ballooning /clarification (according to SAF Activity score)  
Grade 0 
  
 
Grade 1 
  
 
Grade 2 
  
 
 5. Lobular inflammation (according to SAF Activity score) 
Grade 0 
  
 
Grade 1 
  
 
Grade 2 
  
 
 6. Lobular inflammation (according to NASH CRN) 
Grade 0 
  
 
Grade 1 
  
 
Grade 2 
  
 
Grade 3 
  
 


 
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7. Activity score according to SAF (4+5) 
 ____ (to be completed) 
8. NAS according to NASH CRN (3a+4+6) 
 ____ (to be completed) 
9. Portal inflammation:  
 None 
  
 
Mild 
  
 
More than mild 
 
10. Mallory-Denk bodies:  
Absent 
 
Present 
 
11. Fibrosis  
 11a. Fibrosis stage (According to NASH CRN Scoring for Fibrosis):  
Stage 0 
 
Stage 1a 
 
Stage 1b 
 
Stage 1c 
 
Stage 2 
 
Stage 3 
 
Stage 4 
 
 
11b. Fibrosis stage (Adapted from Ishak Scoring for Fibrosis):  
  0=No fibrosis 
 1=Fibrous expansion of portal or central vein area, with or without short fibrous septa 
 2=Fibrous expansion of most portal or central areas, with or without short fibrous septa 
 3=Fibrous expansion of most portal or central areas, with occasional portal to portal 
bridging 
 4=Fibrous expansion of portal or central areas, with marked bridging 
 5=Marked bridging with occasional nodules (incomplete cirrhosis) 
 6=Cirrhosis 
12. Iron overload 
12.a Intensity 
Absent 
 
Mild 
 
Moderate  


 
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Severe 
 
12.b Location 
None 
 
Macrophages  
Hepatocytes  
Both 
 
13. Diagnosis 
Not NAFLD 
 
NAFLD, not NASH  
NASH 
 
 
3. RECOMMENDATIONS FOR SLIDES PREPARATION: 
 Five unstained slides must be prepared by the local pathology laboratory for transfer to the 
central lab 
 In case where unstained slides are not available, stained slides could be accepted (H&E 
plus one slide stained with a staining of fibrous tissue either Masson’s trichrome, 
picrosirius red or reticulin)  
 Fixation and paraffin embedding will be performed according to local procedure 
 Quality of section is crucial. A sharp knife should be used to recut liver sections on a good 
microtome by an experienced technician. Optimal technical quality without knife scratches 
should be obtained. 
 Each slide should be cut 4 microns thick and come from the same liver biopsy core 
whenever possible 
 Sections should be mounted preferably on positively charged slides (Superfrost Plus 
treated slides) 
 Each slide should contain sections 2 cm in length or greater and no less than 15 mm 
PREPARATION AND SHIPMENT OF SLIDES TO THE CENTRAL LABORATORY 
 Place slides in the plastic slide holder  
 Protect the glass slide within the slide holder with adequate material 
 Affix an adequate label on the glass slide and on the outside of the slide holder 
 Ship the slide holder to the central lab using an Ambient shipper  
 Slides will be stained (Hematoxylin & Eosin, Picrosirius red staining, Perls staining) in the 
central histology laboratory. 
PROCEDURE FOR SLIDE READING IN THE DEPARTMENT OF PATHOLOGY 


 
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 Shipment will be received on working hours (from Monday to Friday 8:00 AM to 5:00 
PM) at the department of the Central reader (Liverpat – Pierre Bedossa, 14 avenue d’Eylau, 
75016 Paris, France). 
 The day before the shipment, an e-mail will be sent to Pr Pierre Bedossa. 
(pierre.bedossa@liverpat.com) with mention of the number of samples and patient protocol 
references. 
 On reception in the department of pathology, an authorized person will check the number 
of slides and control that slides are not broken and staining is adequate. In case of problem 
the central lab will be immediately alerted by returned e-mail. 
 In the lab, sections will be transferred to pathologist office for reading. Other slides are 
stored unstained until immunostaining will be performed by batches.  
 After slides reading, the central pathologist will complete a report that will be sent to the 
central lab to be recorded in the study database.  
 The duration between reception of slides and return of eCRF should not exceed 10 working 
days 
 Slides will be stored in department of the central pathologist until the end of the study. 
Upon Investigator’s request, the biopsy slides might be sent back to the site on an ongoing 
basis. 
 


 
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APPENDIX D : SF-36 QUESTIONNARY 
 
In general, would you say your health is:  
a. Excellent  
☐(1) 
b. Very good  
☐(2) 
c. Good   
☐(3) 
d. Fair  
 
☐(4) 
e. Poor 
 
☐(5) 
 
 
Compared to one year ago, how would you rate your health in general now? 
a. Much better now than one year ago  
☐(1) 
b. Somewhat better now than one year ago 
☐(2) 
c. About the same as one year ago 
 
☐(3) 
d. Somewhat worse than one year ago  
☐(4) 
e. Much worse than one year ago 
 
☐(5) 
 
The following items are about activities you might do during a typical day. Does your 
health now limit you in these activities? If so, how much? 
3.1 
Vigorous activities, such as running, lifting heavy objects, participating in 
strenuous sports 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.2 
Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, 
or playing golf 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.3 
Lifting or carrying groceries 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.4 
Climbing several flights of stairs 
a. Yes, limited a lot 
☐(1) 


 
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b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.5 
Climbing one flight of stairs 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all ☐(3) 
3.6 
Bending, kneeling or stooping 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.7 
Walking more than a mile 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.8 
Walking several blocks 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.9 
Walking one block 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
3.10 Bathing or dressing yourself 
a. Yes, limited a lot 
☐(1) 
b. Yes, limited a little 
☐(2) 
c. No, not limited at all 
☐(3) 
 
During the past 4 weeks, have you had any of the following problems with your work 
or other regular daily activities as a result of your physical health?  
4.1 
Cut down on the amount of time you spent on work or other activities 
a. Yes ☐(1) 
b. No ☐(2) 
4.2 
Accomplished less than you would like 
a. Yes 
☐(1) 
b. No 
☐(2) 


 
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4.3 
Were limited in the kind of work or other activities 
a. Yes 
☐(1) 
b. No 
☐(2) 
4.4 
Had difficulty performing the work or other activities (for example, it took extra 
effort) 
a. Yes 
☐(1) 
b. No 
☐(2) 
 
During the past 4 weeks, have you had any of the following problems with your work 
or other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? (Mark each answer with an X) 
5.1 
Cut down the amount of time you spent on work or other activities 
a. Yes 
☐(1) 
b. No 
☐(2) 
5.2 
Accomplished less than you would like 
a. Yes 
☐(1) 
b. No 
☐(2) 
5.3 
Didn’t do work or other activities as carefully as usual 
a. Yes 
☐(1) 
b. No 
☐(2) 
 
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors 
or groups?  
a. Not at all  
☐(1) 
b. Slightly  
☐(2) 
c. Moderately 
☐(3) 
d. Quite a bit 
☐(4) 
e. Extremely 
☐(5) 
 
How much bodily pain have you had during the past 4 weeks?  
a. None  
☐(1) 
b. Very mild 
☐(2) 
c. Mild  
☐(3) 
d. Moderate  
☐(4) 
e. Severe 
☐(5) 
f. Very severe 
☐(6) 
 
During the past 4 weeks, how much did pain interfere with your normal work 


 
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(including both work outside the home and housework) ? 
a. Not at all 
☐(1) 
b. A little bit  
☐(2) 
c. Moderately  
☐(3) 
d. Quite a bit  
☐(4) 
e. Extremely  
☐(5) 
 
These questions are about how you feel and how things have been with you during the 
past 4 weeks. For each question, please give the one answer that comes closest to the 
way you have been feeling. How much of the time during the past 4 weeks – (Mark 
each answer with an X) 
 
All of 
the Time 
(1) 
Most of 
the Time 
(2) 
A Good 
Bit SF-
of the 
Time (3) 
Some 
of the 
Time (4) 
A Little 
of the 
Time (5) 
None of 
the Time 
(6) 
9.1 
Did you feel full of 
pep? 
 
 
 
 
 
 
9.2 
Have you been a very 
nervous person? 
 
 
 
 
 
 
9.3 
 Have you felt so 
down in the dumps 
that nothing could 
cheer you up? 
 
 
 
 
 
 
9.4 
Have you felt calm 
and peaceful? 
 
 
 
 
 
 
9.5 
Did you have a lot of 
energy? 
 
 
 
 
 
 
9.6 
Have you felt 
downhearted and 
blue? 
 
 
 
 
 
 
9.7 
Did you feel worn 
out? 
 
 
 
 
 
 
9.8 
Have you been a 
happy person? 
 
 
 
 
 
 
9.9 
Did you feel tired? 
 
 
 
 
 
 


 
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 During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, 
etc.)?  
f. All of the time  
☐(1) 
g. Most of the time  
☐(2) 
h. Some of the time  
☐(3) 
i. A little of the time  
☐(4) 
j. None of the time 
☐(5) 
 How TRUE or FALSE is each of the following statements for you? 
 
Definit
ely True 
(1) 
Mostly 
True 
(2) 
Don’t 
Know 
(3) 
Mostly 
False 
(4) 
Definit
ely False 
(5) 
11.1 I seem to get sick 
a little easier 
than other people 
 
 
 
 
 
11.2 I am as healthy 
as anybody I 
know 
 
 
 
 
 
11.3 I expect my 
health to get 
worse 
 
 
 
 
 
11.4  My health is 
excellent 
 
 
 
 
 
 
 


 
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APPENDIX E : THE FLINDERS FATIGUE SCALE (FFS) 
FATIGUE SCALE 
 
Name______________________________ 
Date____________________ 
 
We are interested in the extent that you have felt fatigued (tired, weary, exhausted) over the 
last two weeks. We do not mean feelings of sleepiness (the likelihood of falling asleep). Please 
circle the appropriate response in accordance with your average feelings over this two-week 
period. 
 
 
Was fatigue a problem for you? 
0 
1 
2 
3 
4 
Not at all 
 
Moderately 
 
Entirely 
 
Did fatigue cause problems with your everyday functioning (e.g., work, social, family)? 
0 
1 
2 
3 
4 
Not at all 
 
Moderately 
 
Entirely 
 
Did fatigue cause you distress? 
0 
1 
2 
3 
4 
Not at all 
 
Moderately 
 
Entirely 
 
How often did you suffer from fatigue? 
0 
1 
2 
3 
4 
0 
days/week 
1-2 
days/week 
3-4 
days/week 
5-6 
days/week 
7 
days/week 
 
 
 


 
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At what time(s) of the day did you typically experience fatigue? (Please tick box(es)) 
 Early morning  
□ 
 
 
Late afternoon  
□ 
 Mid morning  
□ 
 
 
Early evening  
□ 
 Midday 
 
□ 
 
 
Late evening  
□ 
 Mid afternoon  
□ 
  
 
How severe was the fatigue you experienced? 
0 
1 
2 
3 
4 
Not at all 
 
Moderately 
 
Entirely 
 
 
How much was your fatigue caused by poor sleep? 
 
0 
1 
2 
3 
4 
Not at all 
 
Moderately 
 
Entirely 
 
 

SAP_003.pdf: 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
INVENTIVA 
Study IVA_01_337_HNAS_16_002 
EudraCT  2016-001979-70 
 
 
A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-of-
concept, 24-week treatment study of IVA337 in adult subjects with nonalcoholic 
steatohepatitis (NASH) 
 
 
 
 
Version 1 
May, 13th 2020 
 
 
Sponsor 
CRO 
INVENTIVA SA 
50 rue de Dijon 
21121 Daix 
France 
Keyrus Biopharma – Levallois 
18/20 rue Clément Bayard 
92300 Levallois-Perret 
France 
Philippe Huot-Marchand 
Biostatistician 
Martine Baudin 
Clinical Research Physician 
Nathalie Pillet 
Biostatistician 
 




INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
3/106 
TABLE OF CONTENTS 
 
1 
List of abbreviations and definition of terms _________________________________ 6 
2 
Introduction ___________________________________________________________ 8 
3 
Study description _______________________________________________________ 8 
3.1 
Study objective _____________________________________________________ 8 
3.2 
Study design _______________________________________________________ 8 
3.3 
Study plan ________________________________________________________ 9 
3.4 
Study Population __________________________________________________ 12 
3.4.1 Inclusion Criteria _________________________________________________ 12 
3.4.2 Non-Inclusion Criteria _____________________________________________ 16 
3.4.3 Prohibited concomitant medications __________________________________ 21 
3.4.4 Allowable medications for standard care or precautions __________________ 22 
3.5 
Changes in the conduct of the study __________________________________ 23 
4 
Statistical methods _____________________________________________________ 28 
4.1 
General statistical considerations ____________________________________ 28 
4.1.1 Software used ___________________________________________________ 28 
4.1.2 Statistical deliverables _____________________________________________ 28 
4.1.3 Statistical quality control ___________________________________________ 28 
4.1.4 Descriptive statistics ______________________________________________ 29 
4.1.5 Treatment groups comparison _______________________________________ 29 
4.1.6 Missing data ____________________________________________________ 32 
4.1.6.1 
General considerations ________________________________________ 32 
4.1.6.2 
Dates ______________________________________________________ 32 
4.1.6.3 
Main criteria ________________________________________________ 34 
4.1.7 Handling centres _________________________________________________ 35 
4.1.8 Visit reallocation _________________________________________________ 35 
4.2 
Sample size calculation _____________________________________________ 35 
4.3 
Analysis populations _______________________________________________ 36 
4.3.1 Screened patients _________________________________________________ 36 
4.3.2 Randomized set of patients _________________________________________ 36 
4.3.3 Full analysis set (FAS) ____________________________________________ 36 
4.3.4 Safety set of patients ______________________________________________ 36 
4.3.5 Evaluable patient population (EPP) __________________________________ 36 
4.3.6 Per protocol set of patients _________________________________________ 37 
4.4 
Protocol deviations (PDs) ___________________________________________ 39 
4.5 
Derived variables __________________________________________________ 40 
4.5.1 Baseline data and change from baseline _______________________________ 40 
4.5.2 Disposition data __________________________________________________ 40 
4.5.3 Baseline characteristics ____________________________________________ 42 
4.5.4 Efficacy ________________________________________________________ 45 
4.5.4.1 
Liver biopsy _________________________________________________ 45 
4.5.4.2 
Fibrosis markers _____________________________________________ 47 
4.5.4.3 
Glucose metabolism __________________________________________ 49 


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4.5.5 Questionnaires ___________________________________________________ 49 
4.5.5.1 
Short Form Health Survey (SF-36) _______________________________ 49 
4.5.5.2 
Flinders Fatigue Scale (FFS) ____________________________________ 50 
4.5.6 Safety __________________________________________________________ 50 
4.5.6.1 
Treatment data _______________________________________________ 50 
4.5.6.2 
Adverse Event data ___________________________________________ 53 
4.5.6.3 
Laboratory data ______________________________________________ 54 
4.5.6.4 
Electrocardiogram data ________________________________________ 55 
4.5.6.5 
Vital signs __________________________________________________ 55 
4.6 
Modifications from the statistical section of the protocol _________________ 56 
4.6.1 Terminology ____________________________________________________ 56 
4.6.2 Analysis populations ______________________________________________ 56 
4.6.3 Endpoints _______________________________________________________ 56 
4.6.4 Efficacy analysis _________________________________________________ 57 
4.6.5 Subgroups analysis _______________________________________________ 57 
4.6.6 Liver Iron Content ________________________________________________ 57 
4.7 
Analysis of sub-groups/complementary analysis ________________________ 57 
5 
Statistical analyses _____________________________________________________ 58 
5.1 
Demographic data and other baseline characteristics ____________________ 58 
5.1.1 Patients disposition _______________________________________________ 58 
5.1.2 Protocol deviations _______________________________________________ 59 
5.1.3 Demographic characteristics ________________________________________ 59 
5.1.4 Alcohol consumption _____________________________________________ 59 
5.1.5 Type 2 Diabetes status _____________________________________________ 60 
5.1.6 Metabolic syndrome ______________________________________________ 60 
5.1.7 Liver biopsy _____________________________________________________ 60 
5.1.8 Fibroscan _______________________________________________________ 61 
5.1.9 Anthropometric and vital signs ______________________________________ 61 
5.1.10 
Medical/Surgical history _________________________________________ 61 
5.1.11 
Prior medications _______________________________________________ 61 
5.1.12 
Concomitant medications ________________________________________ 61 
5.1.13 
Pregnancy test _________________________________________________ 62 
5.1.14 
Genotype _____________________________________________________ 62 
5.2 
Efficacy data _____________________________________________________ 63 
5.2.1 Summary of statistical methods _____________________________________ 63 
5.2.2 Primary efficacy analysis __________________________________________ 74 
5.2.2.1 
Primary analysis of the primary endpoint __________________________ 74 
5.2.2.2 
Sensitivity analyses ___________________________________________ 75 
5.2.2.3 
Analysis by subgroups ________________________________________ 75 
5.2.2.4 
Secondary analyses of the primary endpoint ________________________ 75 
5.2.3 Secondary analyses _______________________________________________ 77 
5.2.3.1 
NASH improvement __________________________________________ 77 
5.2.3.2 
Resolution of NASH without worsening of fibrosis __________________ 78 
5.2.3.3 
Improvement of fibrosis by at least 1 stage with no worsening of NASH _ 79 
5.2.3.4 
Resolution of NASH and Improvement of fibrosis by at least 1 stage ____ 82 
5.2.3.5 
Resolution of NASH without worsening of fibrosis and NASH improvement
 
83 


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5.2.3.6 
Change in components Steatosis (CRN-S), Activity (SAF-A), Inflammation 
(CRN-I) and Ballooning (CRN-B) _______________________________________ 84 
5.2.3.7 
Change in component Fibrosis of CRN score and modified Fibrosis Ishak 85 
5.2.3.8 
Glucose metabolism __________________________________________ 88 
5.2.3.9 
Liver enzymes _______________________________________________ 89 
5.2.3.10 Plasma lipids levels ___________________________________________ 90 
5.2.3.11 Efficacy inflammatory markers __________________________________ 92 
5.2.3.12 Efficacy fibrosis markers ______________________________________ 93 
5.2.3.13 Efficacy chemistry markers _____________________________________ 94 
5.2.3.14 Improvement of ISHAK fibrosis by at least 2 stages with no worsening of 
NASH 
95 
5.3 
Safety data _______________________________________________________ 96 
5.3.1 Extent of exposure ________________________________________________ 96 
5.3.2 Display of adverse events __________________________________________ 96 
5.3.2.1 
Overall summary of Treatment Emergent Adverse Events (TEAEs) _____ 96 
5.3.2.2 
Overall Analysis of Treatment Emergent Adverse Events (TEAEs) _____ 97 
5.3.2.3 
Analysis of Non-Treatment Emergent Adverse Events (non-TEAEs) ____ 97 
5.3.2.4 
Analysis of Post-Treatment Adverse Events (PTAEs) ________________ 97 
5.3.2.5 
Analysis of Adverse Events in screen failure patients ________________ 97 
5.3.3 Other safety analysis ______________________________________________ 97 
5.3.3.1 
Specific cardiac inflammatory safety: NT-pro-BNP __________________ 97 
5.3.3.2 
Bone remodelling ____________________________________________ 98 
5.3.3.3 
Laboratory tests for safety assessment ____________________________ 98 
5.3.3.4 
Anthropometric and vital signs __________________________________ 99 
5.3.3.5 
Electrocardiogram (ECG) ______________________________________ 99 
5.4 
Quality of Life ___________________________________________________ 101 
5.5 
Exploratory data _________________________________________________ 102 
5.5.1 Liver biopsy ____________________________________________________ 102 
5.5.2 Fibroscan ______________________________________________________ 102 
5.5.3 Alcohol consumption ____________________________________________ 103 
5.5.4 Immunohistochemistry (semi-quantitative score of ballooning and stellate cell 
activation) ___________________________________________________________ 103 
5.5.5 Pharmacokinetic data ____________________________________________ 103 
6 
Tables, Listings and Graphs (TLG) _______________________________________ 104 
7 
Template of tables, listings and graphs ____________________________________ 104 
8 
Appendix 1 - Correspondence between patient number and country ____________ 104 
9 
Appendix 2 - Contents of statistical deliverables _____________________________ 105 
10 Appendix 3 – Strategy for analysis QC ____________________________________ 105 
11 References ___________________________________________________________ 105 
 
 
 


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1 
List of abbreviations and definition of terms 
 
Abbreviation  
Definition  
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
ANCOVA 
Analysis of Covariance  
AST 
Aspartate Aminotransferase  
BDRM 
Blind Data Review Meeting  
BMI 
Body Mass Index  
CAP 
Controlled Attenuation Parameter  
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel  
CPK 
Creatine PhosphoKinase 
CRF 
Case Report Form 
CRN-B 
CRN Hepatocyte Ballooning score 
CRN-F 
CRN Fibrosis score  
CRN-I 
CRN Lobular Inflammation score  
CRN-S 
CRN Steatosis score  
CS 
Clinically Significant 
DBL 
Data Base Lock 
DBP 
Diastolic Blood Pressure  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EOS 
End Of Study 
EPOS 
Elucidating Pathways of Steatohepatitis 
EPP 
Evaluable patient population  
FAS 
Full Analysis Set 
FFA 
Free fatty acids  
FFS 
Flinders Fatigue Scale  
GGT 
Gamma GT 
HDL 
High Density Lipoproteins 
HLR 
Head Line Results  
HR 
Heart rate  
IMP 
Investigational Medicinal Product (i.e. treatment)  
LDL 
Low Density Lipoproteins 
MCHC 
Mean Corpuscular Haemoglobin Concentration  
MCMC 
Markov chain Monte Carlo  
MCV 
Erythrocytes Mean Corpuscular Volume  
MH 
Medical History  
MMRM 
Mixed Model for Repeated Measures  
NAFLD 
Non Alcoholic Fatty Liver Disease 


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Abbreviation  
Definition  
NAS 
NAFLD Activity Score  
NASH 
Non Alcoholic SteatoHepatitis 
NCS 
Non Clinically Significant 
NFS 
NAFLD Fibrosis Score  
NNT  
Number Needed to Treat 
OC 
Observed Cases  
OCUT 
Observed Cases Under Treatment  
OR 
Odds Ratio  
PD 
Protocol Deviation 
PP 
Per Protocol 
PT 
Preferred Term  
PTAE 
Post Treatment Adverse Events 
QC 
Quality Control 
RBC 
Red Blood Cells 
RR 
Risk Ratio  
SAE 
Serious Adverse Event 
SAF 
Steatosis Activity Fibrosis  
SAF-A 
SAF Activity score  
SAF-F 
SAF Fibrosis score  
SAF-I 
SAF Lobular Inflammation score  
SAF-S 
SAF Steatosis score  
SAP 
Statistical Analysis Plan  
SBP 
Systolic Blood Pressure  
SF-36 
Short Form Health Survey 36 items 
SH 
Surgical History  
SOC 
System Organ Class 
TE 
Transient Elastrography  
TEAE 
Treatment Emergent Adverse Event  
TFLs 
Tables, Figures, Listings 
USA 
United States of America 
WBC 
White Blood Cells 


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2 
Introduction 
 
This document describes the frame of the statistical analysis that will be conducted for the study 
“A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-of-concept, 
24-week treatment study of IVA337 in adult subjects with nonalcoholic steatohepatitis 
(NASH)”. 
 
This Statistical Analysis Plan has been written in agreement with: 
- 
The Clinical Study Protocol version 5.1 dated March 25th, 2020 
- 
The blank electronic Case Report Form (eCRF) version 13.0 dated January, 14th 2020 
- 
The annotated eCRF version 13.0 dated January, 14th 2020 
 
This document will be reviewed, approved and signed by the sponsor of the study 
(Biostatistician and the Clinical Research Physician), before the database lock [DBL]. 
 
This document is the reference document for all the statistical analyses of this study, except the 
analyses presented during DSMB (Data Safety Monitoring Board) meetings and 
pharmacokinetics/pharmacodynamics analyses that will be analysed separately, with specific 
statistical analysis plans developed. 
 
The purpose of this document is to describe: 
- 
The characteristics of the study as defined in the protocol: objectives, design and 
conduct of the study 
- 
The criteria/variables analysed and the derived variables to be created 
- 
The planned statistical analysis and the methodology used. 
 
 
3 
Study description 
 
3.1 
Study objective 
 
The main objective of this IIb, Proof of Concept study is to assess the safety and the efficacy 
on the activity part of the Steatosis Activity Fibrosis (SAF) histological score (inflammation 
and ballooning) of a 24-week treatment with two doses of lanifibranor (IVA337) (800, 1200 
mg/24h) versus placebo in NASH adult patients. 
 
3.2 
Study design 
 
This is a  
- 
Three arm (placebo, lanifibranor (IVA337) 800 and 1200 mg/day),  
- 
Randomised (1:1:1, stratified on diabetes),  
- 
Placebo-controlled,  
- 
Double-blind,  
- 
Parallel-assignment,  
- 
Dose-range,  
- 
Multicenter: at least 60 sites across 13 European countries (i.e., Belgium, France, Italy, 
Spain, United-Kingdom, Poland, Czech Republic, Germany, The Netherlands, 
Switzerland, Austria, Portugal, Slovenia), Canada, Australia, Mauritius and the United 
States of America (USA) will participate,  
- 
24-week treatment study. 


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The study will require at least 30 months of enrolment period, to randomise 225 patients (i.e. 
at least 300 screened patients), for a total study duration of up to 38 months. 
 
The overall study design is shown in Figure below. 
 
 
 
 
3.3 
Study plan 
 
Patients will undergo 6 visits:  
- 
Screening visit (V-1, -8 weeks to -2 weeks) 
- 
Randomisation (V0), 
- 
Interim visit 1 (V1, 4 weeks after V0),  
- 
Interim visit 2 (V2, 14 weeks after V0),  
- 
End of treatment visit (V3, 24 weeks after V0)  
- 
And a follow-up visit (28 weeks after V0).  
 
A detailed list of procedures performed at each visit is presented in Table 1 and Table 2 Table 
1below, depending on whether a liver biopsy of less than 6 months is available before screening 
or not. 
 
 
 
 
 
 
 


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Table 1: Study Schedule of procedures (if a liver biopsy of less than 6 months is available 
before screening) 


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Table 2: Study Schedule of procedures (if a liver biopsy is NOT available before screening) 
 


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3.4 
Study Population 
 
3.4.1 Inclusion Criteria  
 
Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMAN
Y 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZER
LAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
1. 
Adult subjects, age ≥18 years 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2. 
NASH histological diagnosis according to the 
currently accepted definition of both EASL 
2.and AASLD (56,60,61), requiring the 
combined presence of steatosis (any degree ≥ 
5%) + lobular inflammation of any degree + 
liver cell ballooning of any amount, on a liver 
biopsy performed ≤ 6 months before screening 
in the study and confirmed by centralized 
reading during the screening period and  
a. 
SAF Activity score of 3 or 4 (>2)  
b. 
SAF Steatosis score ≥ 1  
c. 
SAF Fibrosis score < 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Additio
n of 
possibilit
y of 
biopsy 
done at 
screenin
g) 
X 
(Addition 
of 
possibilit
y of 
biopsy 
done at 
screening
) 
X 
(Addition 
of 
possibility 
of biopsy 
done at 
screening) 
3. 
Subject agrees to have a liver biopsy performed 
after 24 weeks of treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. 
Compensated liver disease with the following 
hematologic and biochemical criteria on entry 
into protocol:  
- 
ALT < 10xULN  
- 
Hemoglobin > 11 g/dL for females and > 12 
g/dL for males  
- 
White blood cell (WBC) > 2.5 K/μL  
- 
Neutrophil count > 1.5 K/μL  
- 
Platelets > 100 K/μL  
- 
Total bilirubin < 35μmol/L. Patients with 
bilirubin ≥ 35μmol/L can be included if non-
conjugated bilirubin in the setting of a 
Gilbert’s syndrome 
- 
Albumin > 36 g/L  
- 
TP > 80% or INR < 1.4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
(TP > 
80%) 
removed 
X 
(Change 
of unit to 
adapt 
protocol 
units to 
the ones 
of the 
central 
lab 
reports) 
X 
(Change : 
before 
randomiz
ation 
instead of 
on entry 
into 
protocol 
+ 
Hemoglo
bin ≥ 110 
g/L (11 
g/dL) for 
females 
and ≥ 120 


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Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMAN
Y 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZER
LAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
- 
Serum creatinin < 1.3 mg/dL (men) or < 1.1 
mg/dL (women) or estimated glomerular 
filtration rate ≥ 60 mL/min/1.73m2  
g/L (12 
g/dL) for 
males 
+  
Precision 
of range 
in another 
unit 
5. 
No other cause of chronic liver disease 
(autoimmune, primary biliary cholangitis, 
HBV, 
HCV, 
Wilson’s, 
α-1-antitrypsin 
deficiency, hemochromatosis, etc…).  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
(adding 
“consider
ed to have 
an impact 
on the 
patient’s 
safety or 
on the 
efficacy 
evaluation
”  
6. 
If applicable, have a stable type 2 diabetes, 
defined as HgbA1c < 8.5% and fasting 
glycemia <10 mmol/L, no changes in 
medication in the previous 6 months, and no 
new symptoms associated with decompensated 
diabetes in the previous 3 months 
X  
(“decomp
ensated”) 
not 
mentione
d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Correctin
g typo  
+ 
Précision 
of fasting 
glycemia 
in mg/dL 
+ Change 
“no 
change in 
medicatio
n” by “no 
introducti
on of new 
medicatio
n” 


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Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMAN
Y 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZER
LAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
+ Adding 
“Minor 
modificati
ons of 
anti-
diabetic 
treatments 
or 
dosages 
are 
allowed if 
done in a 
context of 
stable 
type 2 
diabetes, 
i.e. 
HbA1c ≤ 
8.5% in 
the 
previous 6 
months” 
7. 
Have a stable weight since the liver biopsy was 
performed defined by no more than a 5 % loss 
of initial body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8. 
Negative pregnancy test or post-menopausal. 
Women with childbearing potential (i.e. fertile, 
following menarche and until becoming post-
menopausal unless permanently sterile) must be 
using 
a 
highly 
effective 
method 
of 
contraception (i.e. combined (estrogen and 
progestogen 
containing) 
hormonal/ 
progestogen-only 
hormonal 
contraception 
associated 
with 
inhibition 
of 
ovulation, 
intrauterine device, intrauterine hormone-
releasing system, bilateral tubal occlusion, 
vasectomised partner). 
The 
contraceptive 
method will have to be followed for at least one 
menstruation cycle after the end of the study. 
X 
 
No 
details 
X 
 
Details on 
definition 
of women 
with 
childbearin
g potential 
and highly 
effective 
method of 
contracepti
on, 
including 
“sexual 
abstinence”
X 
 
Same as 
previous 
with 
mention 
of 
follow-up 
"The 
contracep
tive 
method 
will have 
to be 
followed 
for at 
X 
 
Details on 
definition 
of women 
with 
childbearin
g potential 
and highly 
effective 
method of 
contracepti
on, 
including 
“sexual 
abstinence”
X 
 
Same as 
previous 
without 
mention 
of 
"sexual 
abstinenc
e" 
X 
 
Same as 
previous 
without 
mention of 
"sexual 
abstinence" 
X 
X 
X 
X 
X 


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Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMAN
Y 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZER
LAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
. No 
mention of 
follow-up 
after the 
end of the 
study 
least one 
menstruat
ion cycle 
after the 
end of 
the 
study" 
. No 
mention of 
follow-up 
after the 
end of the 
study 
9. 
Subjects having given her/his written informed 
consent 
X 
(“Subject
s must be 
willing to 
give 
written 
informed 
consent”) 
X 
(“Subjects 
must be 
willing to 
give written 
informed 
consent”) 
X 
(“Subject
s must be 
willing to 
give 
written 
informed 
consent”) 
X 
X 
(“Subject
s must be 
willing to 
give 
written 
informed 
consent”) 
X 
(“Subjects 
must be 
willing to 
give written 
informed 
consent”) 
X 
X 
X 
X 
X 
 
 


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3.4.2 
Non-Inclusion Criteria  
 
Non-Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMA
NY 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZE
RLAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
1. 
Evidence of another form of liver disease 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Adding “considered 
to have an impact 
on the patient’s 
safety or on the 
efficacy 
evaluation.” 
2. 
History of sustained excess alcohol ingestion: 
daily alcohol consumption > 30 g/day (3 drinks 
per day) for males and > 20 g/day (2 drinks/day) 
for females 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adding “History of 
sustained excess 
alcohol ingestion in 
the year before the 
pre-study 
treatment biopsy” 
3. 
Unstable metabolic condition: Weight change > 
5kg in the last three months, diabetes with poor 
glycemic 
control 
(HgbA1c 
> 
8.5%), 
introduction of an antidiabetic or of an anti-
obesity 
drug/malabsorptive 
or 
restrictive 
bariatric (weight loss) surgery in the past 6 
months prior to screening 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Addition 
of “> 11 
lbs” for the 
weight 
change) 
X 
Change : “Weight 
change > 5%” 
+ 
Delete 
“/malabsorptive” 
4. 
History 
of 
gastrointestinal 
malabsorptive 
bariatric surgery within less than 5 years or 
ingestion of drugs known to produce hepatic 
steatosis including corticosteroids, high-dose 
estrogens, 
methotrexate, 
tetracycline 
or 
amiodarone in the previous 6 months 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adding “oral 
corticosteroids”  
+ replace “high 
dose” by ‘(dose 
>5mg/day 
prednisone 
equivalent) 
+ adding tamoxifen 
+ adding 
“Corticosteroids 
administered by 
routes other than 
oral are allowed. 
One short (<2 
weeks) course of 


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Non-Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMA
NY 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZE
RLAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
oral corticosteroids, 
more than 3 months 
before the pre-study 
treatment biopsy is 
also allowed.” 
5. 
Significant systemic or major illnesses other 
than liver disease, including congestive heart 
failure (class C and D of the AHA), unstable 
coronary 
artery 
disease, 
cerebrovascular 
disease, pulmonary disease, renal failure, organ 
transplantation, serious psychiatric disease, 
malignancy that, in the opinion of the 
investigator, would preclude treatment with 
IVA337and/or adequate follow up 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(IVA3
37 
replac
ed by 
lanifib
ranor) 
X 
(IVA337 
replaced by 
lanifibranor
) 
X 
6. 
HBs antigen >0, HCV PCR >0 (patients with a 
history of HCV infection can be included if 
HCV PCR is negative since more than 3 years), 
HIV infection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7. 
Pregnancy/lactation or inability to adhere to 
adequate contraception in women of child-
bearing potential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Replace 
“Pregnancy/lactatio
n” by “Pregnancy or 
lactation” 
8. 
Active 
malignancy 
except 
cutaneous 
basocellular carcinoma.  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
9. 
Any other condition which, in the opinion of the 
investigator would impede competence or 
compliance or possibly hinder completion of 
the study 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
18/106 
Non-Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMA
NY 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZE
RLAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
10. Body mass index (BMI) >45 kg/m2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
11. Type 1 diabetes and type 2 diabetic patient on 
insulin 
X 
 
(Type 2 
diabetic 
patient 
on 
insulin) 
not 
mentione
d 
X 
 
(Type 2 
diabetic 
patient 
on 
insulin) 
not 
mentione
d 
X 
 
(Type 2 
diabetic 
patient 
on 
insulin) 
not 
mentione
d 
X 
 
(Type 2 
diabetic 
patient 
on 
insulin) 
not 
mentione
d 
X 
 
(Type 2 
diabetic 
patient on 
insulin) 
not 
mentione
d 
X 
 
(Type 2 
diabetic 
patient on 
insulin) 
not 
mentione
d 
X 
X 
X 
X 
X 
12. Diabetic ketoacidosis  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
13. Fasting Triglycerides > 300 mg/dL  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adding “(3.39 
mmol/L)”.  
14. Hemostasis disorders or current treatment with 
anticoagulants 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
15. Contra-indication to liver biopsy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
16. History of, or current cardiac dysrhythmias 
and/or a history of cardiovascular disease event, 
including myocardial infarction, except patients 
with only well controlled hypertension. Any 
clinically significant ECG abnormality reported 
by central ECG reading  
X 
 
(Any 
clinically 
significan
t ECG 
abnormal
ity 
reported 
by 
central 
ECG 
reading) 
not 
mentione
d 
X 
 
(Any 
clinically 
significan
t ECG 
abnormal
ity 
reported 
by 
central 
ECG 
reading) 
not 
mentione
d 
X 
 
(Any 
clinically 
significan
t ECG 
abnormal
ity 
reported 
by 
central 
ECG 
reading) 
not 
mentione
d 
X 
 
(Any 
clinically 
significan
t ECG 
abnormal
ity 
reported 
by 
central 
ECG 
reading) 
not 
mentione
d 
X 
 
(Any 
clinically 
significan
t ECG 
abnormal
ity 
reported 
by central 
ECG 
reading) 
not 
mentione
d 
X 
 
(Any 
clinically 
significan
t ECG 
abnormal
ity 
reported 
by central 
ECG 
reading) 
not 
mentione
d 
X 
X 
X 
X 
X 
Adding “confirmed 
by the Investigator 
to be Clinically 
Significant” 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
19/106 
Non-Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMA
NY 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZE
RLAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
17. Participation in any other investigational drug 
study within the previous 3 months  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
18. Have a known hypersensitivity to any of the 
ingredients or excipients of the IMP including: 
Lactose monohydrate, Hypromellose, Sodium 
laurilsulfate, Sodium starch glycolate (type A), 
Magnesium stearate, Opadry™ II 85F18422  
 
X  
 
Ingredien
ts and 
excipient
s not 
detailed 
X 
X  
 
Ingredien
ts and 
excipient
s not 
detailed 
X  
 
Ingredien
ts and 
excipient
s not 
detailed 
X  
 
Ingredien
ts and 
excipient
s not 
detailed 
X 
X 
X 
X 
X 
19. Be possibly dependent on the Investigator or the 
sponsor (e.g., including, but not limited to, 
affiliated employee). 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
20. Creatine phosphokinase (CPK) >5 x ULN 
 
 
X  
 
(ULN) 
not 
mentione
d 
 
 
 
X 
X 
X 
X 
X 
21. Osteopenia or any other well documented Bone 
disease. Patient without well documented 
osteopenia treated with vitamin D and/or 
Calcium based supplements for preventive 
reasons can be included  
  
 
X 
 
 
 
X 
X 
X 
X 
X 
Rewording : 
“Patient 
whitoutwith history 
of well documented 
osteopenia. Patient 
treated with vitamin 
D and/or Calcium 
based supplements 
for preventive 
reasons can be 
included.” 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
20/106 
Non-Inclusion criteria 
Corresponding protocol versions 
 
V1.0 
V1.1 
V1.2 
FRANCE 
V1.2 
GERMA
NY 
V1.2 
SWITZE
RLAND 
V1.3 
SWITZE
RLAND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0  
V5.1 
(The criteria below are applicable only for patients who 
will undergo a MRI/LMS in selected centers) 
22. Claustrophobia to a degree that prevents 
tolerance of MRI scanning procedure. Sedation 
is permitted at discretion of investigator. 
23. Metallic implant of any sort that prevents MRI 
examination including, but not limited to: 
aneurysm clips, metallic foreign body, vascular 
grafts or cardiac implants, neural stimulator, 
metallic contraceptive device, tattoo, body 
piercing that cannot be removed, cochlear 
implant; or any other contraindication to MRI 
examination. 
 
 
 
 
 
 
 
 
X 
X 
X 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
21/106 
3.4.3 Prohibited concomitant medications 
 
Prohibited concomitant 
medications 
Corresponding protocol versions 
V1.0 
V1.1 
V1.2 FRANCE 
V1.2 
GERMANY 
V1.2 
SWITZERLA
ND 
V1.3 
SWITZERLA
ND 
V2.0 
V3.0 
V4.0 
V4.2 
V5.0 
V5.1 
PPAR Gamma agonist, fibrates, 
ezetimibe, bile salts chelators, 
phytosterols, fish oils 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specification 
of “ 
PPAR Alpha 
agonists 
(fibrates)  
X 
Specification 
of “ 
PPAR Alpha 
agonists 
(fibrates) 
X 
Specification 
of “ 
PPAR Alpha 
agonists 
(fibrates) 
Glucagon like peptide-1 receptor 
agonists (liraglutide, exenatide),  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adding “incl” 
before 
liraglutide,exen
atide 
 
X 
Adding “incl” 
before 
liraglutide,exen
atide 
 
X 
Adding “incl” 
before 
liraglutide,exen
atide 
 
Insulin  
 
 
 
 
 
 
X 
X 
X 
X 
X 
Vitamins E (alpha-tocopherol)  
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
Antioxidants 
such as 
vitamins E 
(alpha-
tocopherol) 
X 
X 
X 
Anticoagulants (warfarin, dabigatran, 
rivaroxaban, apixaban)  
X 
Anticoagulants 
without 
specification 
X 
Anticoagulants 
without 
specification 
X 
Anticoagulants 
without 
specification 
X 
Anticoagulants 
without 
specification 
X 
Anticoagulants 
without 
specification 
X 
Anticoagulants 
without 
specification 
X 
X 
X 
Adding “incl” 
before 
warfarin, 
dabigatran, 
rivaroxaban, 
apixaban 
 
X 
Adding “incl” 
before 
warfarin, 
dabigatran, 
rivaroxaban, 
apixaban 
 
X 
Adding “incl” 
before 
warfarin, 
dabigatran, 
rivaroxaban, 
apixaban 
 
Steroids  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral corticosteroids 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
22/106 
3.4.4 Allowable medications for standard care or precautions 
 
- Obesity 
Stable weight since the liver biopsy was performed, defined by no more than a 5 % loss of 
initial body weight  
 
- Treatment used for the underlying medical condition  
Treatments are allowed within certain restrictions (described above and below) and 
provided they have been kept at stable doses for at least 6 months before the pre-
treatment biopsy. 
o Type 2 diabetes: Metformin is allowed as well as dipeptidyl peptidase-4 
inhibitors and sodium-glucose transport protein 2 inhibitors: canagliflozin, 
dapagliflozin and empagliflozin. Glucagon like peptide-1 receptor agonists 
(liraglutide, exenatide) or glitazones are not allowed 
o Hyperlipidemia: only statins at stable doses will be allowed 
o Antiplatelets agents: The antiplatelets agents (aspirin, ticlopidine, clopidogrel, 
prasugrel, ticagrelor) are allowed 
o Herbal supplements and Others Supplementation: Herbal preparations or 
vitamin supplements should not be taken as it is difficult to know exactly what 
they contain and could be liver toxic 
 
- Other Medications  
Medications other than the Investigational Medicinal Product (IMP) and those mentioned above 
must only be taken exceptionally and with the agreement of the investigator in order to avoid 
interference with study assessments. The need for other medication may lead to exclusion of 
the patient from the study.  
If symptomatic medication is needed to treat adverse events related to IMP, the investigator 
will inform the sponsor about the concomitant medication given.  
 
 
 
 
 
 
 
 
 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
23/106 
3.5 
Changes in the conduct of the study 
 
The last version of the protocol is version 5.1, dated March, 25th 2020. The original protocol 
was amended 7 times. The list of exhaustive changes is described in the summary of changes 
from each protocol amendment. 
 
Additionally: 
- It was initially planned to consider ‘at least 60’ sites, and finally 92 sites were involved 
in the study 
- It was initially planned to consider ‘at least 300 patients screened’, and finally 868 
patients were screened 
- It was initially planned to randomise ‘225 patients’, and finally 247 were randomised in 
the study, mainly due to the multicentric nature of the study.  
- As per initial sample size, it was estimated that 100 patients per group were needed to 
be screened to randomise 75 patients, meaning a screening failure rate of 25%. Based 
on collected data, the actual observed screening failure rate is of 72%. 
 
The table below list the application date of each protocol version by country and site: 
 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
24/106 
Country 
Site 
PI 
V 1.0 
V 1.1 
V 1.2 
V 1.3 
V 2.0 
V 3.0 
V4.0 
V4.2 
Version 
28/AUG/2016 
Version 
19/AUG/2016 
Version 
10/FEB/2017 
CH 
Version 
19/NOV/2017 
CH 
Version 
10/MAR/2017 
Version 
02/AUG/2017 
Version 
02/NOV/2017 
Version 
12/DEC/2018 
Australia 
1201 
HODGE 
NA 
NA 
NA 
NA 
NA 
19/01/2018 
11/04/2018 
25/03/2019 
Australia 
1202 
CHINNARATHA 
NA 
NA 
NA 
NA 
NA 
22/12/2017 
23/08/2018 
29/04/2019 
Australia 
1203 
SKOIEN 
NA 
NA 
NA 
NA 
NA 
22/12/2017 
12/06/2018 
04/04/2019 
Australia 
1204 
MULLER 
NA 
NA 
NA 
NA 
NA 
22/12/2017 
24/05/2018 
25/03/2019 
Australia 
1205 
AYONRINDE 
NA 
NA 
NA 
NA 
NA 
29/06/2018 
22/08/2018 
12/04/2019 
Austria 
1001 
TRAUNER 
NA 
28/02/2017 
NA 
NA 
27/06/2017 
10/11/2017 
15/11/2018 
11/01/2019 
Austria 
1002 
STAUBER 
NA 
28/02/2017 
NA 
NA 
27/06/2017 
15/11/2017 
15/11/2018 
11/01/2019 
Belgium 
1 
FRANCQUE 
NA 
23/01/2017 
NA 
NA 
15/05/2017 
16/10/2017 
23/05/2018 
11/01/2019 
Belgium 
2 
LANTHIER 
NA 
23/01/2017 
NA 
NA 
15/05/2017 
16/10/2017 
23/05/2018 
11/01/2019 
Belgium 
3 
MORENO 
NA 
23/01/2017 
NA 
NA 
15/05/2017 
16/10/2017 
23/05/2018 
11/01/2019 
Belgium 
4 
GEERTS 
NA 
NA 
NA 
NA 
NA 
09/02/2018 
19/06/2018 
11/01/2019 
Belgium 
5 
ROBAEYS 
NA 
NA 
NA 
NA 
NA 
09/02/2018 
23/05/2018 
11/01/2019 
Canada 
1301 
SEBASTIANI 
NA 
NA 
NA 
NA 
NA 
15/12/2017 
30/07/2018 
27/02/2019 
Canada 
1302 
STINTON 
NA 
NA 
NA 
NA 
31/07/2017 
12/10/2017 
18/04/2018 
16/01/2019 
Canada 
1303 
BAILEY 
NA 
NA 
NA 
NA 
16/08/2017 
04/10/2017 
11/07/2018 
12/02/2019 
Canada 
1304 
MAROTTA 
NA 
NA 
NA 
NA 
11/10/2017 
31/10/2017 
09/07/2018 
05/03/2019 
Canada 
1305 
TAM 
NA 
NA 
NA 
NA 
16/06/2017 
13/10/2017 
31/05/2018 
26/02/2019 
Canada 
1306 
DESILET 
NA 
NA 
NA 
NA 
NA 
15/12/2017 
21/11/2018 
01/03/2019 
Canada 
1307 
HAMET 
NA 
NA 
NA 
NA 
NA 
01/02/2018 
31/05/2018 
26/02/2019 
Czech Republic 
901 
URBANEK 
NA 
09/11/2016 
NA 
NA 
24/05/2017 
02/11/2017 
20/06/2018 
11/01/2019 
Czech Republic 
902 
SPERL 
NA 
02/03/2017 
NA 
NA 
14/06/2017 
02/11/2017 
18/07/2018 
11/01/2019 
Czech Republic 
903 
HEJDA 
NA 
03/11/2016 
NA 
NA 
01/06/2017 
02/11/2017 
20/06/2018 
11/01/2019 
France 
201 
RATZIU 
NA 
NA 
NA 
NA 
22/05/2017 
03/10/2017 
28/02/2018 
11/01/2019 
France 
203 
LE CLEACH 
NA 
NA 
NA 
NA 
NA 
NA 
28/02/2018 
11/01/2019 
France 
204 
BOURSIER 
NA 
NA 
NA 
NA 
22/05/2017 
03/10/2017 
28/02/2018 
11/01/2019 
France 
205 
ANTY 
NA 
NA 
NA 
NA 
22/05/2017 
03/10/2017 
28/02/2018 
11/01/2019 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
25/106 
Country 
Site 
PI 
V 1.0 
V 1.1 
V 1.2 
V 1.3 
V 2.0 
V 3.0 
V4.0 
V4.2 
Version 
28/AUG/2016 
Version 
19/AUG/2016 
Version 
10/FEB/2017 
CH 
Version 
19/NOV/2017 
CH 
Version 
10/MAR/2017 
Version 
02/AUG/2017 
Version 
02/NOV/2017 
Version 
12/DEC/2018 
France 
206 
NGUYEN-KHAC 
NA 
NA 
NA 
NA 
22/05/2017 
03/10/2017 
28/02/2018 
11/01/2019 
France 
207 
DI MARTINO 
NA 
NA 
NA 
NA 
22/05/2017 
03/10/2017 
28/02/2018 
11/01/2019 
France 
209 
GUILLAUME 
NA 
NA 
NA 
NA 
NA 
03/10/2017 
28/02/2018 
11/01/2019 
France 
210 
DE LEDINGHEN 
NA 
NA 
NA 
NA 
NA 
03/10/2017 
28/02/2018 
11/01/2019 
France 
211 
LARREY 
NA 
NA 
NA 
NA 
NA 
03/10/2017 
28/02/2018 
11/01/2019 
France 
212 
GUYADER 
NA 
NA 
NA 
NA 
NA 
03/10/2017 
28/02/2018 
11/01/2019 
France 
213 
LEVRERO 
NA 
NA 
NA 
NA 
NA 
10/01/2018 
28/02/2018 
11/01/2019 
France 
214 
LEROY 
NA 
NA 
NA 
NA 
NA 
10/01/2018 
28/02/2018 
11/01/2019 
France 
215 
CASTERA 
NA 
NA 
NA 
NA 
NA 
10/01/2018 
28/02/2018 
11/01/2019 
France 
216 
HEZODE 
NA 
NA 
NA 
NA 
NA 
10/01/2018 
28/02/2018 
11/01/2019 
France 
217 
SERFATY 
NA 
NA 
NA 
NA 
NA 
10/01/2018 
28/02/2018 
11/01/2019 
Germany 
801 
SCHATTENBERG 
NA 
NA 
NA 
NA 
21/06/2017 
06/11/2017 
22/11/2018 
11/01/2019 
Germany 
802 
GEIER 
NA 
NA 
NA 
NA 
21/06/2017 
06/11/2017 
22/11/2018 
11/01/2019 
Germany 
803 
MERLE 
NA 
NA 
NA 
NA 
21/06/2017 
06/11/2017 
22/11/2018 
11/01/2019 
Germany 
804 
MANNS 
NA 
NA 
NA 
NA 
21/06/2017 
06/11/2017 
22/11/2018 
11/01/2019 
Germany 
805 
TRAUTWEIN 
NA 
NA 
NA 
NA 
21/06/2017 
06/11/2017 
22/11/2018 
11/01/2019 
Germany 
806 
GOESER 
NA 
NA 
NA 
NA 
NA 
19/01/2018 
22/11/2018 
11/01/2019 
Germany 
807 
BOETTLER 
NA 
NA 
NA 
NA 
NA 
08/02/2018 
22/11/2018 
11/01/2019 
Germany 
808 
HEINZOW 
NA 
NA 
NA 
NA 
NA 
04/04/2018 
22/11/2018 
11/01/2019 
Italy 
101 
BUGIANESI 
NA 
10/07/2017 
NA 
NA 
06/02/2018 
NA 
NA 
12/04/2019 
Italy 
102 
SVEGLIATI BARONI 
NA 
NA 
NA 
NA 
07/06/2018 
NA 
NA 
NA 
Italy 
103 
MIELE 
NA 
14/02/2018 
NA 
NA 
NA 
NA 
NA 
NA 
Italy 
104 
VALENTI 
NA 
NA 
NA 
NA 
01/10/2018 
NA 
NA 
NA 
Italy 
105 
CRAXI 
NA 
18/09/2017 
NA 
NA 
NA 
NA 
NA 
NA 
Italy 
106 
ANDREONE 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
Italy 
107 
LAMPERTICO 
NA 
NA 
NA 
NA 
01/10/2018 
NA 
NA 
NA 


INVENTIVA_NATIVE_SAP_Version1.0_13MAY2020 
 
T_BST_SAP_EN v2.0 
 
26/106 
Country 
Site 
PI 
V 1.0 
V 1.1 
V 1.2 
V 1.3 
V 2.0 
V 3.0 
V4.0 
V4.2 
Version 
28/AUG/2016 
Version 
19/AUG/2016 
Version 
10/FEB/2017 
CH 
Version 
19/NOV/2017 
CH 
Version 
10/MAR/2017 
Version 
02/AUG/2017 
Version 
02/NOV/2017 
Version 
12/DEC/2018 
Italy 
108 
MANGIA 
NA 
NA 
NA 
NA 
11/07/2018 
NA 
NA 
NA 
Italy 
109 
NASCIMBENI 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
Netherlands 
1101 
TUSHUIZEN 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
Poland 
701 
FLISIAK 
NA 
26/01/2017 
NA 
NA 
26/06/2017 
30/11/2017 
23/05/2018 
02/04/2019 
Poland 
702 
PIEKARSKA 
NA 
NA 
NA 
NA 
26/06/2017 
30/11/2017 
23/05/2018 
02/04/2019 
Poland 
703 
TOMASIEWICZ 
NA 
NA 
NA 
NA 
26/06/2017 
30/11/2017 
23/05/2018 
02/04/2019 
Portugal 
601 
CARVALHO 
NA 
03/01/2018 
NA 
NA 
NA 
NA 
14/05/2018 
11/01/2019 
Spain 
501 
ROMERO GOMEZ 
NA 
23/12/2016 
NA 
NA 
19/06/2017 
06/11/2017 
07/03/2018 
11/01/2019 
Spain 
502 
CRESPO 
NA 
23/12/2016 
NA 
NA 
19/06/2017 
06/11/2017 
07/03/2018 
11/01/2019 
Spain 
503 
CALLEJA 
NA 
23/12/2016 
NA 
NA 
19/06/2017 
06/11/2017 
07/03/2018 
11/01/2019 
Spain 
504 
ANDRADE 
NA 
23/12/2016 
NA 
NA 
19/06/2017 
06/11/2017 
07/03/2018 
11/01/2019 
Spain 
505 
AUGUSTIN 
NA 
NA 
NA 
NA 
NA 
06/11/2017 
07/03/2018 
11/01/2019 
Switzerland 
401 
DUFOUR 
NA 
NA 
17/10/2017 
28/11/2017 
NA 
NA 
19/02/2019 
23/09/2019 
Switzerland 
402 
GOOSSENS 
NA 
NA 
17/10/2017 
28/11/2017 
NA 
NA 
19/02/2019 
24/09/2019 
Switzerland 
403 
TERZIROLI  
NA 
NA 
17/10/2017 
28/11/2017 
NA 
NA 
19/02/2019 
25/09/2019 
UK 
301 
MCPHERSON 
NA 
13/02/2017 
NA 
NA 
06/07/2017 
01/11/2017 
22/05/2018 
11/01/2019 
UK 
302 
AGARWAL 
NA 
NA 
NA 
NA 
NA 
12/02/2018 
22/05/2018 
11/01/2019 
UK 
303 
RYDER 
NA 
NA 
NA 
NA 
NA 
12/02/2018 
22/05/2018 
11/01/2019 
Bulgaria 
1501 
MATEVA 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
08/04/2019 
Bulgaria 
1502 
GENOV 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
05/04/2019 
Bulgaria 
1503 
BALABANSKA 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
05/04/2019 
Bulgaria 
1504 
TOMOV 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
15/04/2019 
Bulgaria 
1505 
KATZAROV 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
08/04/2019 
Bulgaria 
1506 
STEFANOVA-PETROVA 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
08/04/2019 
Bulgaria 
1507 
HANDZHIEV 
NA 
NA 
NA 
NA 
NA 
NA 
12/03/2018 
05/04/2019 
France 
218 
KWIATEK 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
31/12/2018 


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Country 
Site 
PI 
V 1.0 
V 1.1 
V 1.2 
V 1.3 
V 2.0 
V 3.0 
V4.0 
V4.2 
Version 
28/AUG/2016 
Version 
19/AUG/2016 
Version 
10/FEB/2017 
CH 
Version 
19/NOV/2017 
CH 
Version 
10/MAR/2017 
Version 
02/AUG/2017 
Version 
02/NOV/2017 
Version 
12/DEC/2018 
Mauritus 
1401 
ROUZIER 
NA 
NA 
NA 
NA 
NA 
NA 
11/04/2018 
13/03/2019 
Poland 
704 
NAPORA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
02/04/2019 
Poland 
705 
HARTLEB 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
02/04/2019 
Slovenia 
1701 
SIBLI 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
11/04/2019 
Slovenia 
1702 
GERIC 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
25/04/2019 
US 
1601 
NEFF 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
28/03/2019 
US 
1602 
HARRISON 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
12/02/2019 
US 
1603 
CALDWELL 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
16/05/2019 
US 
1604 
REINDOLLAR 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
14/06/2019 
US 
1605 
LAZAS 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
15/02/2019 
US 
1606 
SANYAL 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
29/05/2019 
US 
1607 
ABDELMALEK 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
09/05/2019 
US 
1608 
TETRI 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
Cancelled 
US 
1609 
ALKHOURI 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
20/02/2019 
US 
1610 
DENHAM 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
Cancelled 
US 
1611 
CASTANEDA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
12/02/2019 
US 
1612 
LOOMBA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
24/05/2019 
US 
1613 
HALEGOUA-DEMARZIO  
NA 
NA 
NA 
NA 
NA 
NA 
NA 
29/05/2019 
US 
1614 
SYAL 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
08/04/2019 
US 
1615 
MYERS 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
28/03/2019 
US 
1616 
BROWN 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
10/04/2019 
 
 


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4 
Statistical methods 
 
4.1 
General statistical considerations 
 
4.1.1 Software used 
 
All statistical analyses will be performed with the SAS software version 9.4 or higher.  
 
 
4.1.2 Statistical deliverables 
 
Statistical results will be delivered in several batches: 
- the first batch will contain the Head Line Results (HLR) 
- the other batches being all other results described in this Statistical Analysis Plan (SAP). 
 
The contents of the HLR and other results are defined in Appendix 2 - Contents of statistical 
deliverables. 
 
 
4.1.3 Statistical quality control 
 
Derived datasets 
 
For most important derived datasets an independent double programming will be performed 
(Quality Control (QC) type 3): for a given derived dataset, 2 programmers independently write 
a program to produce the dataset; then the 2 datasets obtained by the 2 programmers are 
compared using the SAS® COMPARE procedure; content as well as structure of the 2 datasets 
should be 100% similar. For other datasets a simple control will be performed. Appropriate 
documentation of QC will be developed. 
 
The following deliverables will be provided at time of final analysis: 
- Specifications for derived datasets 
- Analysis datasets in SAS format 
- SAS programs generating the derived datasets 
 
Tables Listing Figures (TFLs) 
 
All SAS programs and TFLs will be programmed and quality controlled by the study SAS 
programmer (self-inspection of the programs/logs and results).  
 
Additionally a QC will be performed by the study biostatistician: 
- Simple programming for all HLR tables (QC type 2):  study biostatistician will use some 
SAS® procedures which allow verifying the statistical results obtained 
- Review of the program and the associated statistical output(s) for non HLR TLFs (QC 
type 1): check of the mean, the standard deviation, the minimum, the maximum for 
quantitative variables, the frequencies and the percentages for the qualitative variables 
and the size of the populations  
Appropriate documentation of QC will be developed.  
 


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The following deliverables will be provided at time of final analysis: 
- Two separate documents compiling all TLFs: one for Appendix 14 and another one for 
Appendix 16.2 
- SAS programs generating the outputs: TFLs 
 
The detailed strategy put in place for HLRs QC (from derived datasets to TFLs) is provided in 
“ 
 
See appended document: INVENTIVA_NATIVE_SAP_Mock_Up_TFLs 
 
 
Appendix 3 – Strategy for analysis QC” of this document.  
 
4.1.4 Descriptive statistics 
 
Continuous variables will be described using: number of non-missing observations (N), number 
of missing observations (Nmiss), arithmetic mean (Mean), standard deviation (SD), minimum 
(MIN), quartile 1 (Q1), median (Median), quartile 3 (Q3) and maximum (MAX). 
MIN, Q1, Median, Q3 and MAX will be given at the data number of decimal points but limited 
to 2 decimals. Mean and SD will be given at 1 additional decimal point but limited to 3 
decimals.  
The 95% two-sided confidence interval (CI) will be calculated when appropriate using the 
standard method (Standard normal distribution). 
 
Categorical variables will be presented using N, Nmiss and percentages (%). Missing data will 
not be included in the denominator for the calculation of percentages. 
Proportions will be displayed with one decimal. 
The 95% two-sided CIs will be calculated when appropriate using the exact (Clopper-Pearson) 
method.  
 
All descriptive statistics will be done by treatment group (Placebo, lanifibranor 800 mg/day and 
1200 mg/day) and overall (for baseline characteristics only). 
 
 
4.1.5 Treatment groups comparison  
 
For statistical tests, the type I error risk of these will be set at 5% (2-sided) without adjustments 
for multiplicity testing, unless specified otherwise.  
 
P-values will be presented with 3 decimals. Any p-value less than 0.001 will be presented as 
<0.001, even if it would normally round up to 0.001. 
 
Hochberg procedure for multiplicity testing  
 
When specified, the ascending Hochberg procedure will be used to adjust for multiplicity 
testing. This procedure is a powerful tool that decreases the false discovery rate: this is the 
expected proportion of "discoveries" (significant results) that are actually false positives. 
Adjusting the rate helps to control for the fact that sometimes small p-values (less than 5%) 
happen by chance, which could lead to incorrectly reject the true null hypotheses. In other 


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words, the procedure helps to avoid type I errors (false positives). To run the procedure, the 
following steps will be followed: 
1. Put the individual p-values (without multiplicity adjustment) in ascending order, from 
smallest to largest. 
2. Assign ranks to the p-values. For example, the smallest has a rank of 1, the second 
smallest has a rank of 2. 
3. Calculate each individual p-value’s critical value, using the formula (i/m)Q, where: 
o i = the individual p-value’s rank, 
o m = total number of tests, 
o Q = the false discovery rate (type I error) 
4. Compare original p-values to the critical ones from Step 3; find the largest p value that 
is smaller than the critical value. 
 
As an example, the following table shows the result of 2 tests (lanifibranor 800 mg vs. placebo 
and lanifibranor 1200 mg vs. placebo) with their p-values. The list of p-values are ordered (Step 
1) and then ranked (Step 2) in the 3rd column. The last column shows the calculation of the 
critical value with a false discovery rate of 5% (Step 3). For instance, last column for test 2 
(lanifibranor 800 mg vs. placebo) is calculated as (2/2) * 0.05 = 0.050: 
 
Test 
p-value observed 
Rank (i) 
(i/m)Q=(i/2)x0.05 
Lanifibranor 
1200 
mg vs. placebo 
0.020 
1 
0.025 
Lanifibranor 800 mg 
vs. placebo 
0.028 
2 
0.050 
 
As the p-value associated to the test “lanifibranor 1200 mg vs. placebo” (p-value = 0.020) is 
smaller than its associated critical value (critical-value = 0.025), the test is considered as 
statistically significant after multiplicity adjustment according to the ascending Hochberg 
procedure. Similarly, the test “lanifibranor 800 mg vs. placebo” is considered as statistically 
significant after multiplicity adjustment according to the ascending Hochberg procedure: p-
value = 0.028 < critical-value = 0.050.  
 
Comparison of treatment groups for quantitative variables will be performed using: 
 
- an Analysis of Covariance (ANCOVA) using the SAS MIXED procedure with  
the treatment and the diabetic status as covariates when specified 
 
Or 
 
- a Mixed Model for Repeated Measures (MMRM) when specified using the SAS 
MIXED procedure with: 
a. The absolute change from baseline of the analysis variable as endpoint (MODEL 
statement of the MIXED procedure) 
b. The time, treatment, the diabetic status, the interaction (treatment * time) and 
the baseline value as fixed effects (MODEL statement of the MIXED 
procedure). Time, treatment and diabetic status being considered as categorical 
variables 
c. A time repeated measure (REPEATED statement of the MIXED procedure) 
within each subject (SUBJECT = subject as option of the REPEATED 


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statement). An unstructured (type=UN) variance covariance matrix being used 
as option of the REPEATED statement 
d. The Kenward-Roger approximation to estimate denominator degrees of freedom 
and adjust standard errors (ddfm=kr option in MODEL statement) 
In order to explore the validity of the model (and more accurately the assumption 
regarding independence, normality and constant variance of residuals), the following 
graphs will be provided: Q-Q plot of the residuals, distribution of residuals with its 
corresponding normal density estimate and scatterplot of residuals vs. predicted values.  
 
With such models (ANCOVA, MMRM) different treatment effects will be evaluated: 
- Evaluation of treatment effect (Each dose vs. placebo) at week 24: In 
order to evaluate each treatment dose versus placebo at week 24 the 
following contrasts of interest will be used: 
o 800 mg/day vs. placebo: -1 for Placebo, 1 for 800 mg/day and 0 
for 1200 mg/day 
o 1200 mg/day vs. placebo: -1 for Placebo, 0 for 800 mg/day and 1 
for 1200 mg/day.  
In order to take into account multiplicity of tests, the ascending Hochberg 
procedure will be applied (see section 4.1.5). 
- Evaluation of dose effect (800 mg vs. 1200 mg) at week 24: In order 
to evaluate the dose of 800 mg/day versus the dose of 1200 mg/day at 
week 24 the following contrast of interest will be used: 
o 800 mg/day vs. 1200 mg/day: 0 for Placebo, -1 for 800 mg/day 
and 1 for 1200 mg/day  
- Time course of the response of each treatment group: In order to 
evaluate the time course of the response of each dose (separately) at each 
time-point the following contrasts of interest will be used for each dose: 
o week 4 vs. week 14: -1 for week 4, 1 for week 14, 0 for week 24 
and 0 for week 28 
o week 4 vs. week 24: -1 for week 4, 0 for week 14, 1 for week 24 
and 0 for week 28 
o week 4 vs. week 28: -1 for week 4, 0 for week 14, 0 for week 24 
and 1 for week 28 
o week 14 vs. week 24: 0 for week 4, -1 for week 14, 1 for week 24 
and 0 for week 28 
o week 14 vs. week 28: 0 for week 4, -1 for week 14, 0 for week 24 
and 1 for week 28 
o week 24 vs. week 28: 0 for week 4, 0 for week 14, -1 for week 24 
and 1 for week 28 
In order to take into account multiplicity of tests, the ascending Hochberg 
procedure will be applied (see section 4.1.5).  
Lowest dose will always be considered as reference for treatment effect calculation. As 
well as earliest visit will always be considered as reference for time course evaluation.  
 
Comparisons of treatment groups for qualitative variables will be done using the FREQ 
procedure with Cochran–Mantel–Haenszel (CMH) test option, stratified on the diabetic status 
at Baseline (yes/no). The primary measure of the effect size will be the CMH odds ratio with 
an adjustment for diabetic status. Because the odds ratio is not easy to interpret when the rate 
of responders in the placebo group is not very small the odds ratio (OR) will be converted in 


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Risk Ratio (RR) using the following formula RR = (P1/P0) = OR/[(1−P0) + (P0×OR)]. The 
same formula will be applied to OR 95% CI lower and upper bounds to obtain RR 95% CI. The 
log-binomial model will preferentially be used in the absence of convergence or estimability 
issue for estimating the effect size with RR. The primary handling of heterogeneity of result 
across strata will be performed through the Breslow-Day test. If the homogeneity hypothesis is 
rejected, then the estimate of the difference in percentage points between each dose and placebo 
along with the 95% C.I. will be provided within each stratum, as well as the p-value of the 
association test between treatment and qualitative variable (Chi-2 test or Fisher's exact test). If 
the interaction between stratum and treatment (Breslow Day test) is significant it means that 
the treatment effect has not the same magnitude in diabetic and non-diabetic patients. In the 
absence of qualitative interaction there will be no further adjustment of the type one error for 
multiplicity of testing. Smallest dose will always be considered as reference for OR/RR 
calculation.  
 
Dose-response relationship for qualitative variables will be estimated using the Cochran-
Armitage trend test via the LOGISTIC procedure (See Reference 5). Within this model, dose 
will be considered as a quantitative covariate (0 mg, 800 mg and 1200mg) and diabetic status 
as a qualitative covariate (Presence, Absence). The p-value assessing the significant dose-
response relationship at week 24 will be provided based on this model (Score test).  
 
 
4.1.6 Missing data 
 
4.1.6.1 General considerations 
 
Unless otherwise specified, missing data will not be replaced. In this case, the descriptive 
analyses of each variable will be based on the available data, i.e. Observed Cases (OC) analysis, 
considering missing data as non-informative. The number of missing data will be documented 
for each analysis. 
 
4.1.6.2 Dates 
 
Imputation rules for missing first dose date / last dose date: 
- Missing first dose date / last dose date at intermediate visits will remain missing 
- Missing first dose date at time of randomisation will be imputed as the date of 
randomisation 
- Missing end dose date at time of Visit 3 will be imputed as follow: 
o If the patient prematurely withdrew from the study due to AE and if the 
month/year of EOT date is equal to month/year of start date of AE, then the EOT 
date will be replaced by the start date of AE 
o If the patient prematurely withdrew from the study due to a reason other than 
AE, then: 
 If last contact date is missing then the date of last visit performed under 
treatment (V3 or V2 or V1) will be considered as the EOT date 
 If last contact date is provided, then it will be considered as the EOT 
date.  
o If the patient completed the treatment period, and if the month/year of EOT date 
is equal to month/year of date of Visit 3, then the EOT date will be replaced by 
the date of Visit 3 
 


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Imputation rules for partial or missing start dates for AE: 
- If month and year are present: 
 If month/year of AE corresponds to month/year of a physical 
examination with an abnormal value and if verbatim of AE corresponds 
to the finding of this physical examination, then impute the day by the 
day of physical examination with an abnormal value 
 Otherwise, if month/year of AE corresponds to month/year of  first 
treatment intake then impute the day with the day of first intake of 
treatment  
 Otherwise, impute by the first day of the month 
- If only the year is present, impute by January 1st of that year. If the year is the same as 
the year of the date of first dose, impute by the day of first intake of treatment. 
- If the start date is entirely missing, impute by the day of first intake of treatment. If after 
imputation AE start date is posterior to AE end date, then imputed start date should be 
replaced by AE end date.        
 
Imputation rules for partial or missing start dates for concomitant medications and medical 
history: 
- If the month and year are present, impute the day by the first of that month. If the month 
and year are the same as those of the date of first dose, impute the day with the day of 
first intake of treatment. 
- If only the year is present, impute by January 1st of that year. If the year is the same as 
the year of the date of first dose, impute by the day of first intake of treatment. 
- If the start date is entirely missing, impute by the day of first intake of treatment. If after 
imputation concomitant medication or medical history start date is posterior to 
concomitant medication or medical history end date, then imputed start date should be 
replaced by concomitant medication or medical history end date.        
 
Imputation rules for partial or missing stop dates for AE, concomitant medication and medical 
history: 
- If the month and year are present, impute the day by the last day of that month. 
- If only the year is present, impute by December 31st of that year. 
- If the stop date is entirely missing, assume the event or medication is ongoing. 
 
 
For any partial dates other than start and stop dates, for AE, concomitant medical and medical 
history: 
- If only month and year are present, impute by 15th of that month,  
- If only the year is present, impute by July 1st of that year 
- If date is fully missing, impute by corresponding visit date.  
 


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4.1.6.3 Main criteria 
 
The following method of missing data imputation will be used for main efficacy criteria analysis 
(qualitative endpoints: Responder vs. Non-responder): 
 
1. Primary imputation method 
Patients with a missing data will be considered as Non-responder.  
 
2. Secondary imputation method 
Patients with a missing data will be considered as Non-responder in case of premature treatment 
withdrawals due to: Adverse event or Other: Lack of efficacy. The other reasons will be clearly 
reviewed during Blind Data Review Meeting (BDRM) to identify ‘Lack of efficacy’. 
In all other cases, missing data will remain missing. 
 
3. Observed cases (OC) 
Missing data will remain missing, only observed cases will be used. 
 
4. Observed cases under treatment (OCUT) 
Biopsy: 
Only observed cases within 14 days after study treatment last intake will be considered: 
- Missing data will remain missing 
- Any biopsy data collected more than 8 days after study treatment last intake will not be 
considered as assessed under treatment, meaning will be considered as missing for the 
OCUT analysis 
 
Safety (Treatment Emergent Adverse Event): 
- Adverse events that started after 28 days will be considered as Post Treatment Adverse 
Events (PTAE) 
 
All other procedures: 
Only observed cases within 3 days after study treatment last intake will be used: 
- Missing data will remain missing 
- Will also be considered as missing any data collected more than 3 days after study 
treatment last intake 
 
Note:  
- Data collected at Visit 3 being an early treatment discontinuation, should not be taken 
into account for Week 24 (i.e. actual V3) data descriptions 
- For OCUT analysis where data available at Week 28 (i.e. V4) should be described, all 
Week 28 (i.e. V4) data that are within 4 weeks ± 2 weeks compared with Week 24 (i.e. 
V3) are to be taken into account.  
Data collected at Visit 4 being the visit following an early treatment discontinuation, 
should not be taken into account for Week 28 (i.e. actual V4) data descriptions 
- For all analysis based on biopsy data, data collected at actual V3 should be taken into 
account as well as data collected at Visit 3 being an early treatment discontinuation. 
 
 
 


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4.1.7 Handling centres 
 
In order to explore any potential “center” or geographical effect on primary criteria, centers 
need to be pooled in order to have enough patients by “group”. 
 
Three strategies of center pooling will be used to explore any potential “center” effect: 
1. Centers will be distributed in 2 groups: Bulgaria (the main recruiter in the study) and all 
other countries 
2. Centers will be distributed in 3 groups according to the number of randomised and 
treated patients (i.e. in the FAS, see section 4.3.3): 
o 3 or less patients randomised and treated 
o From 4 to 9 patients randomised and treated 
o 10 or more patients randomised and treated 
 
 
4.1.8 Visit reallocation 
 
Not Applicable.  
 
 
 
4.2 
Sample size calculation 
 
The expected rate of responders according to the retained definition was estimated to 10% for 
the placebo by a group of clinical experts. An excess rate of responders of 20% was accepted 
as clinically pertinent. It corresponds to a multiplication of chance of success (responders) of 3 
and a NNT (Number Needed to Treat) of 5. The sample size required to reach a power of at 
least 80% is 72 patients per group with a two-sided alpha of 0.025 (adjustment for multiplicity). 
The sample size is sensitive to the rate of responders in the placebo group. For example, if the 
rate of responders is 15% instead of 10% then 85 patients are required. If the true rate is lower 
than 10% then less patients may be sufficient. The sample size is therefore rounded in the 
conservative side of 75 patients per group. 
 
Based on the experience of previous clinical trials, it is estimated that 100 patients per group 
will need to be screened to randomise 75 patients after central reading of liver biopsy confirms 
the NASH diagnosis and activity (screening failure rate of 25%). However, as detailed in 
section 3.5, the observed screening failure rate was of 72%), consistent with all other clinical 
trial performed in NASH with such a high screening failure rate. 
In case the end of study liver biopsy slides are not available or not interpretable in more than 
5% of patients, an amendment will be submitted to increase sample size accordingly. 


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4.3 
Analysis populations 
 
4.3.1 Screened patients 
 
The screened patients will consist of all patients who signed the informed consent (with an 
informed consent date completed). 
 
4.3.2 Randomized set of patients  
 
The randomized set of patients will consist of all randomized patients.  
In case of treatment error, the treatment assigned in the randomization list will prevail over the 
actual received treatment. Additionally, in case of stratification error at randomization, strata 
assigned via the randomization will be taken into account for the analysis. 
Reminder: Randomisation stratified on diabetes (presence/absence). 
 
4.3.3 Full analysis set (FAS)  
 
The full analysis set will consist of all randomized patients who received at least one dose of 
the assigned treatment.  
In case of error in the assignment of treatment, the actual treatment will be used in the FAS 
instead of the treatment assigned in the randomization list.  
Additionally, in case of stratification error at randomization, actual strata will be taken into 
account for the analysis. 
 
4.3.4 Safety set of patients 
 
The safety set of patients will consist of the FAS who will have taken at least one dose of 
treatment, regardless any protocol deviations. ‘No adverse event’ confirmed by the investigator 
in the AE form will be considered as a post-baseline assessment of safety. 
In case of treatment error, the actual treatment will be used.  
  
4.3.5 Evaluable patient population (EPP) 
 
The evaluable patient population will consist of the FAS after exclusion of all patients without 
post-randomization efficacy assessment (SAF score at visit 3). 
- All patients who prematurely discontinued the study treatment: 
o due to a reason linked to study treatment intake (adverse event) or lack of 
efficacy (recorded in ‘Other’) will be included in the EPP. In this case, the 
patient will be non-responder (see ‘Secondary imputation method’ in section 
4.1.6.3).  
o for a reason not linked to study treatment intake (such as lost to follow-up or 
consent withdrawal) will be excluded from the EPP.  
The reasons of study treatment premature discontinuation will be solely reviewed during 
BDRM to correctly define the EPP.  
- Patients that completed their study treatment up to Visit 3: 
o with an efficacy assessment at Visit 3 (biopsy performed, readable and 
performed within 14 days following last intake) will be included in the EPP.  
o without efficacy assessment at Visit 3 (biopsy not performed because patient 
refusal, biopsy not readable, biopsy not performed within 14 days following last 
intake…) will be excluded from the EPP. 


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The same rule will be applied for other binary efficacy variables. 
 
4.3.6 Per protocol set of patients 
 
This set will be composed of all patients of the FAS free from major protocol deviation, which 
can bias the estimate of the treatment effect. Patients with major deviations will be listed during 
the Blind Data Review Meetings and the reason for exclusion will be provided. Post-treatment 
biopsy evaluable for efficacy not available will be considered as a major protocol deviation. 
 
The figure below summarizes the patient populations to be considered: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: 
When considering actual treatment received: 
- if a patient received both active and placebo IMPs during the study, active IMP will be 
considered as actual treatment  
Screening 
V3 (week 24) 
Evaluable 
Not evaluable 
Completed patient at week 24 
 
Biopsy available 
at V3  
Biopsy not performed 
/ not interpretable / 
Patient refusal / 
Biopsy performed but 
not readable 
Biopsy available at 
time of premature 
withdrawal 
Reason for withdrawal 
= consent withdrawal, 
lost to FUP, sponsor 
decision … 
Safety set (Treated) 
FAS (Randomised and treated) 
EPP (Evaluable) 
Reason for withdrawal 
= lack of efficacy or   
safety concern 
Biopsy available for efficacy analyses 
Biopsy not under treatment (‘Not 
under treatment’ is a major deviation) 
PP (Excluding other 
major deviations) 
Biopsy under 
treatment  
Treatment prematurely withdrawn before week 24 


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- if a patient received active IMP at both doses (800 mg and 1200 mg) during the study 
due to dispensation error(s), the dose of 1200 mg will be considered as actual treatment  


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4.4 
Protocol deviations (PDs) 
 
The list of PDs has already been developed (see Excel file appended to BDRM minutes named 
“INVEN_21507_Native_Deviation”).  
 
All PDs will be carefully identified through eCRF data before the BDRMs. During the BDRMs 
held before database lock (DBL), each PD will be classified as leading to exclusion from the 
PP population (“major”) or not leading to exclusion from the PP population (“minor”).  
 
All PDs related to study inclusion or non-inclusion criteria, conduct of the trial, patient 
management or patient assessment will be described, such as: 
- Violation of inclusion criteria 
- Violation of exclusion criteria 
- Intake of non-allowed concomitant medications during the treatment period 
- Randomisation error 
- Lack of compliance 
- Primary endpoint not assessable (missing post-treatment biopsy results) 
- Etc. 
 
Additionally, the PDs that could not be identified through eCRF data will also be reviewed 
during the BDRMs. This listing will be based on the PD forms completed by the study monitors. 
These PDs will be extracted from the listing and imported in the database.  
 
 


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4.5 
Derived variables 
 
4.5.1 Baseline data and change from baseline 
 
Baseline data will be considered as the last available non-missing data before or equal to the 
treatment start.  
 
Note: For biopsies, multiple reading rules (see section 4.5.4.1.1) should be applied before 
calculating Baseline values.  
 
Absolute change from baseline will be calculated as follows: 
Value at Vi – Value at baseline, where i corresponds to a post-baseline value. 
 
Relative change from baseline (in %) will be calculated as follows: 
- if Value at baseline is not equal to 0: [(Value at Vi – Value baseline) / Value at baseline] 
* 100, where i corresponds to a post-baseline value. 
- if both values at Vi and at baseline are equal to 0, then the relative change from baseline 
will be equal to 0%. 
 
Regarding laboratory parameters that are sensitive to the fasting status (Fasting Glucose, 
HOMA, insulin, C-peptid, Fructosamine, Triglycerides, Total cholesterol, HDL cholesterol, 
LDL cholesterol, Free fatty acids (FFA), Apoprotein A1, Apoprotein B, Apoprotein C3, 
Adiponectin, Leptin, FGF-21): 
- if the value at Baseline is a non-fasting value when the value at Screening is a fasting 
value, then the Baseline data will be the value at Screening 
- if both values at Screening and Baseline are non-fasting values, then the Baseline data 
will be the value at Baseline. 
 
Regarding laboratory parameters, the following status will be defined: 
- Normal-Normal, if the baseline is within laboratory ranges and all values over time 
remain with laboratory ranges 
- Normal-Abnormal, if the baseline is within laboratory ranges but at least one value over 
time is not within laboratory ranges  
- Abnormal-Normal, if the baseline is not within laboratory ranges and all values over 
time are within laboratory ranges  
- Abnormal-Abnormal, if the baseline is not within laboratory ranges and at least one 
value over time is not within laboratory ranges  
 
 
4.5.2 Disposition data 
 
- 
Visit performed 
 
A visit will be considered as performed, if a visit date is reported for this visit. 
 
- 
Patient still under treatment, if visit performed 
 
A patient will be considered as “still under treatment” at a given visit if last treatment intake is 
≥ visit date - 3.  
 


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- 
Patient still ongoing, if visit NOT performed 
 
A patient will be considered as “still ongoing” at a given theoretical visit if another visit has 
been performed after this missing one. 
 
- 
Patient still under treatment, if visit NOT performed 
 
A patient will be considered as “still under treatment” at a given theoretical visit if last treatment 
intake is ≥ theoretical visit date - 3. 
 
- 
Study duration (months) 
 
Study duration (in months) is defined as the time between the randomisation date and the date 
of End of Study: (Date of End of Study – randomisation date + 1) / 30.4375. 
 
- 
Study duration (weeks) 
 
Study duration (in weeks) is defined as the time between the randomisation date and the date 
of End of Study: (Date of End of Study – randomisation date + 1) * 52 / 365.25.  
 
- 
Premature treatment withdrawal 
 
A patient will be considered as having prematurely discontinued study treatment if the reason 
for end of treatment is different from “Treatment period terminated as per protocol”. 
 
- 
Completer patients  
 
A patient will be considered as a completer if he/she did not prematurely withdrawn treatment. 
   
 


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4.5.3 Baseline characteristics 
 
- 
Age 
 
Age (in years) is the one reported in the eCRF.  
 
Patients could be classified in 2 categories according to their age: 
- <65, ≥65 years old 
 
 
- 
Body Mass Index (kg/m²) 
 
Body Mass Index (BMI) is equal to the ratio between the weight (in kg) and the square of the 
height (in meter). 
 
Patients will be classified in 6 categories according to their BMI: 
- Underweight: BMI < 18.5 kg/m² 
- Normal: BMI in [18.5 - 25[ kg/m² 
- Overweight: BMI in [25 - 30[ kg/m² 
- Obese class I (moderate): BMI in [30 - 35[ kg/m² 
- Obese class II (severe): BMI in [35 - 40[ kg/m² 
- Obese class III (morbid): BMI ≥ 40 kg/m²  
 
They will also be classified in 2 categories according to their BMI: 
- Non-obese: BMI < 30 kg/m² 
- Obese: BMI ≥ 30 kg/m²  
 
 
- 
Metabolic Syndrome at Baseline 
 
A patient will be considered as presenting a metabolic syndrome at Baseline when at least 3 of 
these parameters are verified (see Reference 1): 
- Waist circumference ≥ 94 cm/37 inches in men, ≥ 80 cm/31.5 inches in females 
- ‘Hypertension’ reported in Medical History and ticked as ‘ongoing’  
o HYPERTENSION (MedDRA PT code=10020772), 
o DIASTOLIC HYPERTENSION (MedDRA PT code=10012758), 
o ESSENTIAL HYPERTENSION (MedDRA PT code=10015488 
- Pre-diabetic/diabetic condition: Actual ‘Type 2 diabetes mellitus’=Presence or Fasting 
glucose ≥ 100 mg/dl (5.6 mmol/L) if ‘Type 2 diabetes mellitus’=Absence 
- Serum triglycerides > 150 mg/dL (i.e. 1.7 mmol/L) or corresponding Medical History 
reported  
o HYPERTRIGLYCERIDEMIA (MedDRA PT code=10020869), 
o FAMILIAL HYPERTRIGLYCERIDEMIA (MedDRA PT code=10059183),  
o HYPERLIPIDAEMIA (MedDRA PT code=10062060),  
o DYSLIPIDAEMIA (MedDRA PT code=10058108) 
- HDL cholesterol < 40 mg/dL (i.e. 1.0 mmol/L) in men, < 50 mg/dL (i.e. 1.3 mmol/L) in 
females  
 
 
 


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- 
Insulin-resistant status 
 
- Insulin-resistant: Actual ‘Type 2 diabetes mellitus’=Presence or Fasting glucose ≥ 100 
mg/dl (5.6 mmol/L) if ‘Type 2 diabetes mellitus’=Absence 
- Non insulin-resistant: Fasting glucose < 100 mg/dl (5.6 mmol/L) and ‘Type 2 diabetes 
mellitus’=Absence 
 
 
- 
Prior medication 
 
A prior medication corresponds to any medication reported in the “PREVIOUS AND 
CONCOMITANT MEDICATIONS” form of the eCRF with an end date < first treatment intake 
date (after application of missing dates replacement rules, see section 4.1.6.2) 
 
 
- 
Concomitant medication 
 
A concomitant medication corresponds to any medication reported in the “PREVIOUS AND 
CONCOMITANT MEDICATIONS” form of the eCRF with a {start date ≤ first treatment 
intake date and an end date ≥ first treatment intake date or ongoing} or with a {first treatment 
intake date ≤ start date ≤ last treatment intake date} (after application of missing dates 
replacement rules, see section 4.1.6.2) 
 
- 
Antidiabetic treatment  
 
Four antidiabetic classes will be defined:  
o Metformin 
 CMDECOD in ("METFORMIN HYDROCHLORIDE" 
"METFORMIN" "METFORMIN EMBONATE" "DAPAGLIFLOZIN 
PROPANEDIOL MONOHYDRATE W/METFORMIN" 
"EMPAGLIFLOZIN W/METFORMIN HYDROCHLORIDE" 
"EUCREAS" "JENTADUETO" "KOMBIGLYZE" "RISTFOR") 
o Sulphonylurea  
 WHODDrug ATC code = A10BB 
o DPP4i 
 WHODDrug ATC code = A10BH or CMDECOD in ("EUCREAS" 
"JENTADUETO" "KOMBIGLYZE" "RISTFOR") 
o SGLT2 
 CMDECOD in ("DAPAGLIFLOZIN PROPANEDIOL 
MONOHYDRATE" "CANAGLIFLOZIN" "DAPAGLIFLOZIN 
PROPANEDIOL MONOHYDRATE W/METFORMIN" 
"EMPAGLIFLOZIN W/METFORMIN HYDROCHLORIDE" 
“DAPAGLIFLOZIN”) 
 
A patient will be considered as taking at least one antidiabetic treatment if at least one 
treatment detailed above is received.  
 
- 
Statins  
 
- HMG-CoA reductase inhibitors (WHODDrug ATC code: C10AA) 


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- HMG-CoA reductase inhibitors in combination with other lipid modifying agents 
(WHODDrug ATC code: C10BA) 
 
 
 
- 
Time between screening biopsy and randomisation (months) 
 
Time between screening biopsy and randomisation (in months) is defined as the time between 
the date of screening biopsy and the date of randomisation: (Date of randomisation –date of 
screening biopsy + 1) / 30.4375 


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4.5.4 Efficacy  
 
4.5.4.1 Liver biopsy 
 
4.5.4.1.1 Multiple reading at Baseline or V3 
 
In case of multiple reading for a given biopsy at Baseline or at V3, the following strategy needs 
to be applied: 
- If  unreadable assessment : choose readable one 
- If all are unreadable, the biopsy results will be considered as missing 
- If  more than 1 readable assessment :  
o Choose the worst case scenario based on the SAF-A score 
o If both SAF-A scores are similar: 
 Choose the worst scenario based on the SAF-F score 
 If both SAF-F scores are similar: 
 Choose the last reading based on reading date 
 
 
4.5.4.1.2 Biopsy not performed as an efficacy endpoint  
 
Some patients have underwent biopsies during the study that cannot be considered as the 
biopsies to be analysed for efficacy. These biopsies were identified during data cleaning 
process, and were actually reported as ‘unscheduled’ biopsies in the clinical database, in order 
to differentiate them with the biopsies evaluable for efficacy, reported at Visit 3 (week 24). 
 
 
4.5.4.1.3 Available biopsy at V3 (Week 24) 
 
Biopsy will be considered as available at Week 24 if SAF-A is non-missing for a biopsy 
reported at V3 (or for a re-test of a biopsy reported at V3). It will be considered as non-available 
in all other cases.  
 
Reason for non-availability will be considered as: 
- 
“Treatment Prematurely Withdrawn” for all non-completers patients  
- 
"Non-Readable" if biopsy has been performed at V3 and SAF-A is missing for any 
completer patient 
- 
 “Patient Refusal" if reason for not having performed a biopsy at Visit 3 contains ("NOT 
AGREE" "REFUS" "NOT WANT") for any completer patient 
 
 
4.5.4.1.4 Terminology 
 
In the biopsy database, several scores are provided including: 
- 
The SAF Steatosis score (SAF-S) and the CRN Steatosis score (CRN-S) that are similar  
- 
The SAF Lobular Inflammation score (SAF-I) and the CRN Lobular Inflammation score 
(CRN-I) that may slightly differ. Indeed, score of 1 for SAF-I could be grade 2 for CRN-
I.    


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- 
The Hepatocyte Ballooning score, considered as the CRN Hepatocyte Ballooning score 
(CRN-B)  
- 
The SAF Activity score (SAF-A) that is already derived in the database, and that 
corresponds to the sum of SAF-I and CRN-B 
- 
The CRN NAS score (NAS) that will be defined as the NAS score (NAS). This 
parameter is already derived in the database, and corresponds to the sum of CRN-S, 
CRN-I and CRN-B 
- 
The SAF Fibrosis score (SAF-F) and the CRN Fibrosis score (CRN-F) that may slightly 
differ. Indeed values 1a 1b and 1c for the CRN-F are graded as 1 for SAF-F. In the 
analyses, stages 1a 1b and 1c for CRN-F will be considered as stage 1.  
 
4.5.4.1.5 Biopsy length 
 
Available biopsy length will be classified as ≤ 8 mm or > 8 mm. 
 
 
4.5.4.1.6 Response according to SAF activity score (Primary endpoint) 
 
Response is defined as a decrease from baseline to Week 24 of at least 2 points of the SAF 
Activity score (SAF-A) without worsening of the CRN Fibrosis score (CRN-F). No worsening 
means that score remains stable or decreases.   
 
  
4.5.4.1.7 NASH improvement 
 
Improvement is defined as a decrease of at least 2 points of the NAS score (NAS) from baseline 
to Week 24 without worsening of the CRN Fibrosis score (CRN-F).  
 
 
4.5.4.1.8 Resolution of NASH without worsening of fibrosis 
 
Resolution of NASH at Week 24 without worsening of fibrosis is defined as: 
 CRN Lobular inflammation score (CRN-I) equal to {0, 1} at week 24 and 
 CRN Hepatocyte ballooning score (CRN-B) equal to 0 at week 24 and 
 No worsening of the CRN-F score from baseline to week 24.  
 
 
4.5.4.1.9 Improvement of liver fibrosis ≥ 1 stage and no worsening of NASH 
 
Improvement of liver fibrosis ≥ 1 stage and no worsening of NASH is defined from baseline 
to week 24 as: 
 Improvement of CRN-F score ≥ 1 stage and 
 No increase of CRN-S score and 
 No increase of CRN-I score and 


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 No increase of CRN-B score  
 
4.5.4.1.10 Resolution of NASH and Improvement of liver fibrosis ≥ 1 stage 
 
Resolution of NASH and Improvement of liver fibrosis ≥ 1 stage is defined as: 
 CRN Lobular inflammation score (CRN-I) equal to {0, 1} at week 24 and 
 CRN Hepatocyte ballooning score (CRN-B) equal to 0 at week 24 and 
  Improvement of CRN-F score ≥ 1 stage from baseline to week 24 
 
4.5.4.1.11 Resolution of NASH without worsening of fibrosis and NASH improvement  
 
Resolution of NASH at Week 24 without worsening of fibrosis and NASH improvement are 
defined as: 
 CRN Lobular inflammation score (CRN-I) equal to {0, 1} at week 24 and 
 CRN Hepatocyte ballooning score (CRN-B) equal to 0 at week 24 and 
 Decrease of at least 2 points of the NAS score (NAS) from baseline to week 24 
 No worsening of the CRN-F score from baseline to week 24.  
 
4.5.4.1.12 Improvement of ISHAK liver fibrosis ≥ 2 stages and no worsening of NASH 
 
Improvement of ISHAK liver fibrosis ≥ 2 stages and no worsening of NASH is defined from 
baseline to week 24 as: 
 Improvement of ISHAK-F score ≥ 2 stages and 
 No increase of CRN-S score and 
 No increase of CRN-I score and 
 No increase of CRN-B score  
 
4.5.4.2 Fibrosis markers 
 
4.5.4.2.1 NAFLD Fibrosis Score (NFS) 
 
NAFLD Fibrosis Score is to be calculated using the following formula: -1.675 + 0.037 * age 
(years) + 0.094 * BMI (kg/m²) + 1.13 * (Impaired Fasting Glucose/diabetes (yes = 1, no = 0)) 
+ 0.99 * (AST/ALT ratio (no unit)) – 0.013*platelets (×109/L) – 0.66*albumin (g/dl) 
(See Reference 2) 
 
The variable ‘Impaired Fasting Glucose/diabetes (yes = 1, no = 0)’ corresponds to the insulin-
resistant status (Yes, No).  
  
A variable predicting the fibrosis will be constructed from the NFS:  
 Low probability of fibrosis F3/F4 if score is less or equal to -1.455 (included),  
 Fibrosis status indeterminate if -1.455 < score < 0.676,  


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 High probability of fibrosis F3/F4 if score is greater or equal to 0.676 (included).  
 
4.5.4.2.2 FIB-4 score 
 
FIB-4 score is to be calculated using the following formula: (age (years) * AST (U/L)) / 
(platelets (×109/L) * √ALT (U/L)) 
(See Reference 3) 
 
A variable predicting the fibrosis will be constructed from the FIB-4 score:  
 Low probability of fibrosis F3/F4 if score is less to 1.45 (excluded),  
 Fibrosis status indeterminate if 1.45 ≤ score ≤ 3.25,  
 High probability of fibrosis F3/F4 if score is greater to 3.25 (excluded).  
 
4.5.4.2.3 ELF Score 
 
ELF score is to be calculated using the following formula: 2.494 + 0.846 ln(Hyaluronic acid) 
+ 0.735 ln(PIIINP) + 0.391 ln(TIMP-1) 
(See Reference 4) 
 
A variable predicting the fibrosis will be constructed from the ELF:  
 A score less than 7.7 (excluded) indicates no to mild fibrosis 
 A score between 7.7 (included) and 9.8 (excluded) indicates moderate fibrosis 
 A score between 9.8 (included) and 11.3 (excluded) indicates severe fibrosis 
 A score greater or equal to 11.3 (included) indicates cirrhosis.  
 
4.5.4.2.4 MACK-3 Score 
 
MACK-3 score is to be derived using the computation tool available at the website 
http://forge.info.univ-angers.fr/~gh/wstat/mack3-calculator.php (last access on 16JAN20120). 
 
The score is based on the following parameters: AST (IU/L), Glycaemia (mmol/l), Insulin 
(µU/ml) and Cytokeratin M30 (IU/L). 
(See Reference 6) 
 
A variable predicting the fibrosis will be constructed from the MACK-3 score:  
 If Non metabolic syndrome and AST <35 IU/L: No fibrosis 
 If Metabolic syndrome and/or AST ≥35 IU/L: 
o Score less or equal than 0.134 (included): No fibrosis 
o Score between 0.135 (included) and 0.549 (included): Fibrosis undefinable (grey 
zone) 
o Score greater or equal to 0.550 (included): Fibrosis 
 


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4.5.4.2.5 FIBC3 Score 
 
FIBC3 score is to be calculated using the following formula: -5.939 + (0.053*Age in years) + 
(0.076*BMI in kg/m²) + (1.614*T2DM (yes = 1, no = 0)) – (0.009*platelets in 10^9/L) + 
(0.071*PRO-C3 in ng/ml) 
(See Reference 8) 
 
4.5.4.2.6 ABC3D Score 
 
The derived “ABC3D” score comprises: A = Age>50 years, B = BMI>30 kg/m², C = platelet 
Count<200x10^9/L, 3 = PRO-C3>15.5 ng/ml, D = Diabetes = present.  
The presence of each factor scores 1 point, except for T2DM that scores 2 points, yielding to a 
maximum of 6 (See Reference 8) 
 
4.5.4.3 Glucose metabolism 
 
Available HOMA index will be classified as < 3 or ≥ 3. 
 
4.5.5 Questionnaires 
 
4.5.5.1 Short Form Health Survey (SF-36) 
 
Purpose: 
 
SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These 
measures rely upon patient self-reporting and are now widely utilized by managed care 
organizations and by Medicare for routine monitoring and assessment of care outcomes in adult 
patients. 
 
Description: 
 
The SF-36 is “a multi-purpose, short-form health survey with only 36 questions”. It yields an 
8-scale profile including functional health, and mental health. 
 
 
 
Derivation: 
 
A specific tool will be provided with the SF-36 questionnaire to calculate the score of the 8 sub-
dimensions defined above, as well as the physical component score (PCS) and mental 
component score (MCS). Each score will be norm-based from 0 to 100. 


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Interpretation: 
 
All questions are scored on a scale from 0 to 100, the minimum score is 0 (corresponding to a 
poor health) and maximum is 100 (corresponding to a good health). 
 
Reference: 
 
QualityMetric Health Outcomes Scoring Software User’s guide 
 
 
4.5.5.2 Flinders Fatigue Scale (FFS) 
 
Purpose: 
 
The FSS is a self-report questionnaire, designed to measure daytime fatigue. 
 
Description: 
 
It is a relatively brief measure, containing only 7 items that provide a global measure of fatigue. 
 
Each item ranks from 0 (not at all) to 4 (extremely), except item 5 for which patient need to tick 
the time(s) of the day where fatigue is experienced (among 7 possible times).  
 
Derivation: 
 
Global score can be calculated by summing scores on all items as 0 (not at all) through 4 
(entirely), except for item 5 (for this item, sum each time of day that is ticked). 
 
Interpretation: 
 
Global score ranges from 0 to 31 and higher scores indicate greater fatigue. 
 
Reference: 
 
See Reference 7 
 
 
4.5.6 Safety 
 
4.5.6.1 Treatment data 
 
- 
Date of first study intake 
 
Minimum of all “date of first intake after previous visit” reported in “Treatment 
COMPLIANCE” sections of the eCRF. 
 
- 
Date of last study intake 
 
“Date of end of study treatment” reported on the “END OF TREATMENT” form of the eCRF.  


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- 
Treatment duration (months) 
 
Treatment duration (in months) is defined as the time between the first treatment intake date 
and the date of last treatment intake: (Date of last intake – date of first intake + 1) / 30.4375.  
 
- 
Treatment duration (weeks) 
 
Treatment duration (in weeks) is defined as the time between the first treatment intake date and 
the date of last treatment intake: (Date of last intake – date of first intake + 1) * 52 / 365.25.  
 
- 
Compliance at Visit(i) 
 
The compliance (%) at Visit(i) (Vi) corresponds to the ratio between the number of tablets taken 
and the expected number of tablets to be received between the study first treatment intake and 
visit Vi. 
 
Tablets taken: 
 
The number of tablets taken between Vi-1 and Vi is equal to the sum of: 
- {Real/Estimated number of tablets taken at Vi} on all bottles not returned at visit i 
(in case of missing returned bottle) 
OR 
- {38 - Number of tablets returned at Vi} on all bottles returned at visit i (in case of 
returned bottle) 
[38 is the number of tablets per bottle given to the patient every one month (from V1 to V3)] 
 
The total number of tablets taken between study first treatment intake to Vi corresponds to the 
sum of the number of tablets taken in each bottle from study first treatment intake to Vi. 
 
[Indeed, patient should take 3 tablets twice a day, i.e. one tablet twice a day from each of the 
bottles A, B, and C] 
 
If at a given visit the status of at least one bottle (returned / not returned) is not returned or 
missing, or if a corresponding number of “Real/Estimated number of tablets taken” or “Number 
of tablets returned” is missing, then the compliance will be considered as being not evaluable. 
 
Tablets to be received at Visit(i): 
 
The total number of tablets to be received at Visit(i) is equal to: 
(Visit(i) date – Study first treatment intake date + 1)*3 
[Indeed, patient should take 3 tablets, i.e. one tablet from each of the containers A, B, and C 
each morning] 
 
The compliance (%) for a given visit is defined as: 
 Total number of tablets taken between study first treatment intake to Vi / Total number 
of tablets to be received between study first treatment intake to Vi * 100 
 


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- 
Overall persistence 
 
The persistence (%) corresponds to the ratio between the actual number of tablets taken and the 
expected number of tablets to be received between the study first treatment intake and last 
treatment intake. 
 
Tablets taken: 
 
The total number of tablets taken corresponds to the sum of the number of tablets taken in each 
bottle at each visit. 
 
See definition above (in section Compliance at Visit(i)).  
 
Tablets to be received: 
 
The total number of tablets to be received is equal to:  
(Study last treatment intake date – Study first treatment intake date + 1) *3 
 
- 
Overall compliance at time of biopsy at week 24 (when biopsy results at week 24 
are available) 
 
Overall compliance can be calculated as the ratio between actual number of tablets taken 
between first intake and time of biopsy at week 24, and the theoretical number of tablets to be 
received up to the time of biopsy at week 24: 
 
Tablets taken: 
 
The total number of tablets taken corresponds to the sum of the number of tablet not returned 
compared to the number of pills dispensed. 
 
If the date of last intake reported on the EOT form is ≤ date of post-treatment biopsy then tables 
taken is equal to the number of tables taken up to Visit 3 (see definition above in section 
compliance at visit(i)).  
 
If the date of last intake reported on the EOT form is > date of post-treatment biopsy then tables 
taken is equal to the number of tables taken up to Visit 3 (see definition above in section 
compliance at visit(i)) minus 3*(Date of last intake reported on the EOT form - date of post-
treatment biopsy).  
 
 
Tablets to be received up to the time of biopsy at week 24:  
 
The total number of tablets to be received is equal to:  
((Date of biopsy at week 24 – Study first treatment intake date + 1) *3)  
 
 
 
 
 


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- 
Overall compliance at time of biopsy at week 24 (when biopsy results at week 24 
are available) based on lanifibranor bottles 
 
The overall compliance based on lanifibranor bottles can be calculated as the actual number of 
lanifibranor tablets taken and the theoretical number of lanifibranor tablets to be received up to 
the time of biopsy at week 24: 
 
Lanifibranor tablets taken: 
 
The total number of lanifibranor tablets taken corresponds to the sum of the number of 
lanifibranor tablets taken in each bottle at each visit. 
 
If the date of last intake reported on the EOT form is ≤ date of post-treatment biopsy then tables 
taken is equal to the number of tables taken up to Visit 3 (see definition above in section 
compliance at visit(i)).  
 
If the date of last intake reported on the EOT form is > date of post-treatment biopsy then tables 
taken is equal to the number of tables taken up to Visit 3 (see definition above in section 
compliance at visit(i)) minus 3*(Date of last intake reported on the EOT form - date of post-
treatment biopsy).  
 
Lanifibranor tablets to be received up to the time of biopsy at week 24:  
 
The total number of lanifibranor tablets to be received is equal to:  
- (( Date of biopsy at week 24 – Study first treatment intake date + 1) *3) for 
patients receiving lanifibranor at the dose of 1200 mg 
- ((Date of biopsy at week 24 – Study first treatment intake date + 1) *2) for 
patients receiving lanifibranor at the dose of 800 mg 
 
 
4.5.6.2 Adverse Event data 
 
- 
Treatment Emergent Adverse Event 
 
A Treatment Emergent Adverse Event (TEAE) corresponds to an Adverse Event (AE) that 
occurred on or after first dose of treatment up to 28 days post-last dose. 
 
- 
Treatment Emergent Adverse Events related to study treatment 
 
TEAE related to treatment is defined as a TEAE having a relationship to treatment equals to 
“Possibly related”, “Probably related” or with a missing relationship to study treatment. 
 
Relationship equals to “Unlikely Related” will be considered as not related. 
 
- 
Non-Treatment Emergent Adverse Events (non-TEAEs) 
 
Non-TEAEs are AEs that occurred prior to treatment start. 
 
- 
Post-Treatment Adverse Events (PTAEs) 
 


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PTAEs are AEs that occurred more than 28 days after end of treatment. 
 
- 
Serious Adverse Events 
 
By definition, a serious AE (SAE) is an AE that, at any time, fulfils one or more of the following 
criteria: 
- 
results in death, 
- 
is life threatening (the subject was at immediate risk of death at the time of the event; it 
does NOT refer to an event which hypothetically might have caused death if it were 
more severe), 
- 
requires in-subject hospitalisation or prolongation of existing hospitalisation, 
- 
results in persistent or significant disability/incapacity (substantial disruption of a 
person’s ability to carry out normal life functions), 
- 
is a congenital anomaly/birth defect, 
- 
is any important medical event that may not be immediately life threatening or result in 
death or hospitalisation but, based upon appropriate medical judgment, may endanger 
the subject or may require intervention. 
 
The seriousness of the event will be directly assessed by the investigator (specific variable 
within the AE database); therefore no derivation is needed.   
 
- 
Onset day 
 
Onset day is defined as the time between the first treatment intake date and AE onset date: (AE 
onset date – date of first intake + 1).  
 
 
4.5.6.3 Laboratory data 
 
When result is ‘<x’, value to be considered will be ‘x-0.01’ 
When result is ‘>x’, value to be considered will be ‘x+0.01’ 
 
If after the following replacement a value become < 0 then value is forced to 0.  
 
Baseline will be defined as the last available value before or the same day as first treatment 
intake. 
 
Before first treatment intake, the last non-missing value before first intake will be selected.  
 
After first treatment intake, in case of retest for a given parameter, the first non-missing value 
will be selected. 
 
Regarding laboratory parameters that a sensitive to fasting status (Fasting Glucose, HOMA, 
insulin, C-peptid, Fructosamine, Triglycerides, Total cholesterol, HDL cholesterol, LDL 
cholesterol, Free fatty acids (FFA), Apoprotein A1, Apoprotein B, Apoprotein C3, Adiponectin, 
Leptin, FGF-21): 
 
If the status is ‘not fasting’ and the value remains within laboratory ranges, then this value will 
be considered as ‘fasting’ for the analysis. This is applicable for the baseline value (See section 
4.5.1) as well as all values collected over time. 


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4.5.6.4 Electrocardiogram data 
 
In case of retest for a given parameter: 
- Before first treatment intake, the last non-missing value will be selected 
- After first treatment intake the first non-missing value during a visit will be selected 
 
Available QTcF will be classified in 3 distinct categories:  
- 
> 450 or ≤ 450 ms  
- 
> 480 or ≤ 480 ms  
- 
> 500 or ≤ 500 ms.  
 
QTcF prolongation (Absolute change in QTcF from baseline) will be classified in 2 distinct 
categories: 
- 
≥ 60 ms and < 60 ms 
- 
≥ 30 ms and < 30 ms. 
 
Available HR (Heart Rate) will be classified as:  
- 
< 40 beats/min, ≥ 40 and ≤ 120 beats/min, >120 beats/min  
 
Relative change in HR from baseline will be classified as: 
- 
≤ 25 % and >25%  
 
 
 
4.5.6.5 Vital signs  
 
In case of retest for a given parameter: 
- Before first treatment intake, the last non-missing value will be selected 
- After first treatment intake the first non-missing value during a visit will be selected 


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4.6 
Modifications from the statistical section of the protocol  
 
4.6.1 Terminology  
 
In the protocol as well as in this SAP, the terminology ‘modified ISHAK fibrosis’ score is used, 
that was the terminology used at time of initial protocol development. 
Since 2018, both terminologies ‘modified ISHAK fibrosis’ and ‘EPOS’ score (Elucidating 
Pathways of Steatohepatitis’) are used for the same scoring system. 
No change has been performed in the SAP, but this information is given as a note for the 
reviewer. 
 
4.6.2 Analysis populations 
 
The following adjustments in analysis populations are to be highlighted: 
- 
Addition of the “screened patients” population to be able to describe the non-
randomised patients and the corresponding reasons for non-randomisation 
- 
The “Set of evaluable patient” is called “Evaluable patient population (EPP)” in the 
current SAP. The definition of this population has been detailed in order to avoid any 
confusion at time of analysis   
- 
For the “Safety set of patients” the notion “and who have at least one post-baseline 
assessment of safety” has been suppressed as ‘No adverse event’ confirmed by the 
investigator in the AE form will be considered as a post-baseline assessment of safety. 
- 
The following precision has been added for : 
o Randomized set of patients: in case of stratification error at randomization, strata 
assigned via the randomization will be taken into account for the analysis. 
o Full analysis set (FAS): in case of stratification error at randomization, actual 
strata will be taken into account for the analysis. 
 
4.6.3 Endpoints 
 
Some additional information have been added in the SAP in order to clearly explain which 
biopsies should be taken into account for efficacy analysis at week 24 (cases of biopsies with 
multiple reading, efficacy vs. safety biopsies, definition of available biopsies): see sections 
4.5.4.1.1 to 4.5.4.1.3.   
 
The following secondary endpoints have been added: 
- 
NASH improvement (see section 4.5.4.1.7) 
- 
Resolution of NASH and Improvement of liver fibrosis ≥ 1 stage (see section 4.5.4.1.10) 
- 
Resolution of NASH without worsening of fibrosis and NASH improvement (see 
section 4.5.4.1.11) 
- 
Improvement of ISHAK liver fibrosis ≥ 2 stages and no worsening of NASH (see 
section 4.5.4.1.12) 
- 
Fibrosis markers: NAFLD Fibrosis Score (NFS), FIB-4 score, ELF Score, MACK-3 
Score, FIBC3 Score and ABC3D Score (see section 4.5.4.2) 
- 
No worsening of CRN-F score and modified Fibrosis Ishak score (modified ISHAK-F) 
The analysis of the following parameters has been added too: 
- 
Quality of Life: SF-36 and Flinders Fatigue scale (FFS) 


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- 
Pharmacokinetic data 
 
4.6.4 Efficacy analysis 
 
The analysis of dose response relationship has been added in the SAP for primary criterion (see 
section 5.2.2.4) as well as an analysis which explores the evaluation of treatment effect after 
adjustment on the relative change in weight from baseline (see section 5.2.2.4).  
 
4.6.5  Subgroups analysis 
Several subgroups analyses were added (see section 4.7).  
 
4.6.6 Liver Iron Content 
 
In section 6.3.5 Biobank Sample from the protocol, the liver iron content was expected to be 
collected. However, this parameter was not measured by central laboratory and therefore won’t 
be analysed. The pathologist involved in the central reading of biopsies confirmed that iron 
overload intensity (collected in the biopsy form) can be used as a rough estimation for liver iron 
content.  
The iron overload intensity will be analysed (see sections 5.1.7 and 5.5.1).  
 
 
 
4.7 
Analysis of sub-groups/complementary analysis  
 
Subgroup analysis described thereafter, will not be performed if there are not enough patients 
(i.e. less than 15% in one category).  
 
 
Main subgroups of interest are: 
- 
Diabetic status at baseline (Yes, No) 
- 
Biopsy length at baseline (≤ 8, >8 mm) 
- 
NAS score at baseline (< 6, ≥ 6) 
- 
SAF-A score at baseline (A2-A3, A4) 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
- 
BMI at baseline (Obese, Non-obese) 
- 
Metabolic syndrome at baseline (Yes, No) 
- 
Insulin-resistance status at baseline (Yes, No) 
- 
By site group No. 1 (Bulgaria, all other countries) 
- 
By site group No. 2 (3 or less patients randomised and treated, from 4 to 9 patients 
randomised and treated, 10 or more patients randomised and treated) 
- 
Sex (Male, Female) 
 


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5 
Statistical analyses 
 
5.1 
Demographic data and other baseline characteristics 
 
Descriptive analysis will be performed according to the methods detailed in section 4.1.4. 
 
All analysis (except disposition by country) will be provided overall and then according to 
diabetic status at Baseline.  
 
Analysis performed in the FAS will be repeated in the PP population if the difference between 
the 2 populations FAS and PP is ≥ 5%.  
 
As the eCRF has changed during the conduct of the study, some sections/variables may not be 
applicable in some patients.  
 
 
5.1.1 Patients disposition 
 
The number (%) of patients included in each population will be described overall and then by 
country: screened patients, non-randomised patients, randomised patients, FAS, EPP, safety 
patients and PP patients. Percentages will be calculated over the number of randomised patients.  
 
First Patient First Visit, Last Patient First Visit and Last Patient Last Visit will also be described 
overall and then by country. “First Visit” will be defined as the screening visit (V-1).  
 
The reasons for non-randomisation will also be described among the non-randomised patients, 
consisting of screening failed patients.  
 
In addition, in order to have an overview of patients’ disposition, the following elements will 
be described by treatment group and overall in the FAS for each post-randomisation visit: 
- 
Number (%) of patients who performed the visit (Yes/No) 
o If Yes, Number (%) of patients still under treatment (Yes/No) 
o If No: 
 Number (%) of patients still ongoing (Yes/No) 
 Number (%) of patients still under treatment (Yes/No) 
Due to the CRF design, Visit 3 was either completed per protocol and performed at week 24, 
or performed as part of early termination visit. For analysis, visit 3 will be splitted in 2:  
 Visit 3 performed as part of early termination visit (i.e. premature EOT)  
 Visit 3 performed as part of week 24 visit.   
Same strategy will be applied for visit 4: 
 Visit 4 performed after a visit 3 performed as part of early termination 
visit (i.e. follow-up visit following premature EOT)  
 Visit 4 performed at week 28 after a visit 3 performed as part of week 24 
(i.e. follow-up visit following treatment completed until week 24).   
Additionally, for visit 4 performed after a visit 3 as part of week 24, it will be detailed whether 
visit 4 has been performed within 4 weeks +/- 2 weeks after visit 3 or not.  
 
In order to have an overview of biopsies’ disposition, the following elements will be described 
at Visit 3 by treatment group and overall in the FAS 
- 
Number (%) of biopsies available (Yes/No) 


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- 
If Yes, Number (%) of biopsies still under treatment (Yes/No), i.e. within maximum 14 
days after last intake 
- 
If No, Number (%) of  biopsies non-available (non-readable, patient refusal, premature 
permanent treatment discontinuation)  
 
Additionally, patients’ treatment status (Treatment completed, Treatment prematurely 
withdrawn) at time of study end will be described in the FAS overall and by treatment group. 
 
Last visit performed; as well as study duration (weeks) will also be described in the FAS overall 
and by treatment group. 
 
In case of premature study treatment discontinuation (with or without follow-up visit(s) 
performed), reason for premature treatment discontinuation will be described: Adverse Event, 
Lost to follow-up, Treatment stopped upon sponsor request, Consent withdrawn, Withdrawal 
by patient + Adverse Event, other. Other reasons will also be summarized (Forbidden 
concomitant treatment, Patient was not available due to personal reasons, IMP issue the patient 
refused to received it, Withdrawal by patient).   
  
Treatment duration (weeks) will also be described for all patients from the FAS.  
 
5.1.2 Protocol deviations  
 
All PDs for randomised patients will be presented by patient in data listings, with a distinction 
between PD leading to exclusion from the PP population (“major PD, meaning major impact 
on efficacy”)  and not leading to exclusion from the PP population (“minor PD, meaning no or 
minor impact on efficacy”). 
 
Number (%) of patients with at least one PD, with at least one major PD and with at least one 
minor PD will be summarized overall and by treatment group, and by type. A listing of all PDs 
recorded will also be provided. The total number of PDs and the total number of “major” and 
“minor” PDs will be presented in the BDRM document. 
 
All PDs will be reviewed before DBL during the BDRMs.  
 
 
5.1.3 Demographic characteristics 
 
- 
Country, 
- 
Sex (Male, Female), 
- 
Age (years), 
- 
Age in class (<65, ≥65 years old), 
- 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other). 
 
 
5.1.4 Alcohol consumption 
 
- 
Alcohol consumption at screening (Yes, No) 
o If yes, drinks/day, by sex 
- 
Alcohol consumption between screening and V0 (Yes, No) 


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o If yes, drinks/day, by sex 
 
A footnote will be provided in the table defining the ‘Alcohol consumption’. 
 
 
5.1.5 Type 2 Diabetes status 
 
- 
Type 2 diabetes status as reported in the randomisation tool (Yes, No) 
- 
Actual type 2 diabetes status (Yes, No) 
 
 
5.1.6 Metabolic syndrome 
 
- 
Presence of metabolic syndrome at Baseline (Yes, No) 
A footnote will be provided in the table defining the ‘Presence of metabolic syndrome’. 
- 
Mean number of features involved in the metabolic syndrome definition at Baseline 
- 
Number of features involved in the metabolic syndrome definition at Baseline (0, 1, 2, 
3, 4, 5) 
- 
Waist circumference ≥ 94 cm/37 inches in men, ≥ 80 cm/31.5 inches in females (Yes, 
No) 
- 
Hypertension (Yes, No) 
- 
Type 2 diabetes mellitus = Presence or Fasting glucose ≥ 100 mg/dl (5.6 mmol/L) if 
‘Type 2 diabetes mellitus’=Absence (Yes, No),  
- 
Serum triglycerides > 150 mg/dL (i.e. 1.7 mmol/L) or hypertriglyceridemia / 
hyperlipidaemia / dyslipidaemia reported as medical history (Yes, No) 
- 
HDL cholesterol < 40 mg/dL (i.e. 1.0 mmol/L) in men, < 50 mg/dL (i.e. 1.3 mmol/L) 
in females (Yes, No) 
- 
Insulin-resistance status at Baseline (Yes, No) 
 
 
5.1.7 Liver biopsy  
 
- 
Timing of the biopsy (At Screening, Within the past 6 months) 
- 
Time between screening biopsy and randomisation (months) 
- 
CRN-S score (S0, S1, S2, S3) 
- 
CRN-S (quantitative) 
- 
CRN-I score (Grades 0, 1, 2) 
- 
CRN-I (quantitative) 
- 
CRN-B score (Grades 0, 1, 2) 
- 
CRN-B (quantitative) 
- 
CRN NAS score (from 0 to 8) 
- 
CRN NAS score (quantitative) 
- 
SAF-I score (Grades 0, 1, 2) 
- 
SAF-I (quantitative) 
- 
SAF-A score (A2, A3, A4) 
- 
SAF-A score (A2-A3, A4) 
- 
SAF-A (quantitative) 
- 
CRN-F score (F0, F1, F2, F3) 
- 
CRN-F score (F0-F1, F2-F3) 
- 
CRN-F score (quantitative) 


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- 
Fibrosis Stage (modified Ishak) (Stages 0, 1, 2, 3, 4, 5, 6) 
- 
Fibrosis Stage (modified Ishak) (quantitative) 
- 
Biopsy length (mm) 
- 
Biopsy length (≤ 8, >8 mm) 
- 
Iron overload intensity (Absent, mild, moderate, severe) 
- 
Iron overload location (None, Macrophages, Hepatocytes, Both) 
 
 
5.1.8 Fibroscan 
 
- 
Fibroscan performed 
- 
Probe used (M, XL) 
- 
Transient Elastrography (TE) / Stiffness (kPa) 
- 
Controlled Attenuation Parameter (CAP) (dB.m-1) 
 
 
5.1.9 Anthropometric and vital signs  
 
- 
Weight (kg), 
- 
Height (cm), 
- 
BMI (kg/m²), 
- 
BMI in class (Underweight, Normal, Overweight, Obese class I (moderate), Obese class 
II (severe), Obese class III (morbid)) 
- 
BMI in class (Non-obese, Obese)  
- 
Waist circumference (cm) (overall and by sex) 
- 
Systolic Blood Pressure (mmHg), 
- 
Diastolic Blood Pressure (mmHg), 
- 
Heart rate (bpm). 
 
 
5.1.10 Medical/Surgical history  
 
The number (%) of patients with at least one Medical History (MH) or Surgical History (SH) 
will be presented and corresponding MH/SH will be described by MedDRA System Organ 
Class (SOC) and Preferred Term (PT) in the FAS, in a decreasing frequency order. This will be 
done for all Medical History (MH) / Surgical History (SH); then it will be repeated on ongoing 
ones at baseline only.  
 
5.1.11 Prior medications 
 
The number (%) of patients with at least one prior medication will be presented and 
corresponding medications will be described by Medication Class (ATC2 levels) and 
Medication Name in the FAS. 
 
5.1.12 Concomitant medications 
 
The number (%) of patients with at least one concomitant medication will be presented and 
corresponding medications will be described by Medication Class (ATC2 levels) and 
Medication Name in the FAS. 
 


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The analysis will be done on all concomitant medications in a first time. Then it will be repeated 
on the following treatments of interest: 
- 
Antidiabetic treatments administered, see section 4.5.3. 
- 
Statin treatments administered, see section 4.5.3. 
 
The number (%) of patients with at least one concomitant medication will be presented overall 
(all antidiabetic treatments) and for each antidiabetic treatment of interest and for each statin 
treatment.  
 
 
5.1.13 Pregnancy test 
 
- 
Pregnancy test performed (Yes, No) 
- 
If test not performed 
o Reason (Post-menopausal, Other) 
- 
If test performed 
o Test result (Negative, Positive)  
 
5.1.14 Genotype 
 
- 
Genotype performed (Yes, No) 
- 
If genotype performed 
o PNPLA3 result 
o TM6FS2 result  
 


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5.2 
Efficacy data  
 
5.2.1 Summary of statistical methods 
 
To summarize, following efficacy analyses will be provided: 
 
o Primary endpoint: 
Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Response according to 
SAF activity score 
Main analysis (Primary 
analysis of the primary 
endpoint) 
Descriptive 
Treatment effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
Randomised set – Primary imputation method 
PP – Observed cases under treatment 
EPP – Secondary imputation method  
FAS – Observed Cases 
Subgroups analysis(1) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
Secondary analyses 
Dose response relationship 
Dose effect: CMH 
Site effect: CMH 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
PP – Observed cases under treatment 
Treatment effect after adjustment on the 
relative change in weight from baseline: 
Logistic 
FAS - Observed Cases under treatment 
 
 
 
 


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o Secondary endpoints: 
Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
NASH improvers 
Main analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
Dose response relationship 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
EPP – Secondary imputation method 
Dose response relationship 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Subgroups analysis(2) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Resolution of NASH 
without worsening of 
fibrosis 
Main analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
Dose response relationship 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
EPP – Secondary imputation method 
Dose response relationship 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Subgroups analysis(3) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Improvement of fibrosis 
with no worsening of 
NASH 
Main analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
Dose response relationship 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
EPP – Secondary imputation method 
Dose response relationship 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Subgroups analysis(3) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Resolution of NASH and 
Improvement of fibrosis 
Main analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
Dose response relationship 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
EPP – Secondary imputation method 
Dose response relationship 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Subgroups analysis(4) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Resolution of NASH 
without worsening of 
fibrosis and decrease of 2 
points of the NAS score 
Main analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
Dose effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Improvement of ISHAK 
fibrosis with no 
worsening of NASH 
Main analysis 
Descriptive 
Treatment effect: CMH 
Dose response relationship 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Dose response relationship 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Improvement of CRN-S 
Main analysis 
Descriptive 
Treatment effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Improvement of CRN-I 
Main analysis 
Descriptive 
Treatment effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Improvement of CRN-B 
Main analysis 
Descriptive 
Treatment effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
PP – Observed Cases under treatment 
Change in CRN-S 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Sensitivity analysis 
Descriptive 
PP – Observed Cases under treatment 
Change in SAF-A 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Sensitivity analysis 
Descriptive 
PP – Observed Cases under treatment 
Change in CRN-I 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Sensitivity analysis 
Descriptive 
PP – Observed Cases under treatment 
Change in CRN-B 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Sensitivity analysis 
Descriptive 
PP – Observed Cases under treatment 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Improvement/No 
worsening of CRN-F 
Main analysis 
Descriptive 
Treatment effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
PP – Primary imputation method 
Subgroups analysis:  
CRN-F score at baseline 
(F0-F1, F2-F3) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
Improvement/No 
worsening of           
modified-ISHAK-F 
Main analysis 
Descriptive 
Treatment effect: CMH 
FAS – Primary imputation method 
Sensitivity analysis 
Descriptive 
Treatment effect: CMH 
FAS – Observed Cases under treatment 
PP – Primary imputation method 
Subgroups analysis:  
CRN-F score at baseline 
(F0-F1, F2-F3) 
Descriptive 
FAS – Primary imputation method 
FAS – Observed Cases under treatment 
Change in CRN-F 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Sensitivity analysis 
Descriptive 
PP – Observed Cases under treatment 
Subgroups analysis:  
CRN-F score at baseline 
(F0-F1, F2-F3) 
Descriptive 
FAS – Observed Cases under treatment 
Change in modified-
ISHAK-F 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Sensitivity analysis 
Descriptive 
PP – Observed Cases under treatment 
 
 
 
 
 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Glucose metabolism 
(fasting glucose, insulin, 
HOMA index, C-peptid, 
HbA1c and fructosamide) 
Main analysis 
Descriptive  
Treatment effect: MMRM or ANCOVA 
Time course: MMRM when possible 
FAS – Observed Cases under treatment (considering only 
fasting values, when specified) 
Subgroups analysis 
(diabetic status) 
(HbA1c at for HbA1c) 
Descriptive 
FAS – Observed Cases under treatment (considering only 
fasting values, when specified) 
Liver enzymes (ALT, 
AST, GGT, Alkaline 
Phosphatase, Total 
Bilirubin) 
Main analysis 
Descriptive 
Treatment effect: MMRM 
Time course: MMRM 
FAS – Observed Cases under treatment 
Subgroup analysis  
(diabetic status) 
Descriptive 
FAS – Observed Cases under treatment 
Plasma lipids levels (TC, 
HDL-C, LDL-C, TG, 
apoA1, FFA, Adiponectin, 
Leptin, APO B, APO C3 
and FGF21) 
Main analysis 
Descriptive 
Treatment effect: MMRM or ANCOVA when 
specified 
Time course: MMRM when possible 
FAS – Observed Cases under treatment considering only 
fasting values 
Subgroup analysis ;  
- diabetic status 
- statins at Baseline 
Descriptive 
 
FAS – Observed Cases under treatment considering only 
fasting values 
Efficacy inflammatory 
markers (fibrinogen, hs-
CRP, alpha2 
macroglobulin, 
haptoglobin, IL-13, IL-17a, 
, IL-6, IL-1b, TNF-a, 
INFg) 
Main analysis 
Descriptive  
Treatment effect: ANCOVA when specified 
FAS – Observed Cases under treatment 
 
 
 


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Objectives/Endpoints 
Type of analysis 
Method of analysis 
Population and imputation method 
Efficacy fibrosis markers 
(TIMP-1, TIMP-2, 
Hyaluronic acid, P3NP, 
NFS, FIB-4 score, ELF 
score, MACK-3, FIBC3, 
ABC3D, Cytokeratin M30, 
Cytokeratin M65, Liver 
iron content, MMP2, 
MMP9, Pro-C3) 
Main analysis 
Descriptive 
Treatment effect: ANCOVA when specified 
FAS – Observed Cases under treatment 
Exploratory analysis 
Cross-tabulation with the CRN-F score (F0-F1, 
F2-F3) when specified 
FAS – Observed Cases under treatment 
Efficacy chemistry markers 
(Plasma Iron, Transferrin, 
Ferritin) 
Main analysis 
Descriptive 
FAS – Observed Cases under treatment 
Subgroups of interest are : 
(1) 
• 
Biopsy length (≤ 8, >8 mm) 
• 
SAF-A at Baseline (A2-A3, A4) 
• 
CRN-F at Baseline (F0-F1, F2-F3) 
• 
NAS score at baseline (<6, ≥6) 
• 
BMI at Baseline (Obese, Non-Obese)Metabolic syndrome at Baseline (Yes, No) 
• 
Insulin-resistance status at Baseline (Yes, No) 
• 
Sex (Male, Female) 
(2) 
• 
NAS score at baseline (<6, ≥6) 
(3) 
• 
Biopsy length (≤ 8, >8 mm) 
• 
SAF-A at Baseline (A2-A3, A4) 
• 
CRN-F at Baseline (F0-F1, F2-F3) 
• 
NAS score at baseline (<6, ≥6) 
• 
BMI at Baseline (Obese, Non-Obese)Metabolic syndrome at Baseline (Yes, No) 
• 
Insulin-resistance status at Baseline (Yes, No) 
• 
By site group No. 1 (Bulgaria, all other countries) 
• 
By site group No. 2 (3 or less patients randomised and treated, from 4 to 9 patients randomised and treated, 10 or more patients randomised and treated) 
• 
Sex (Male, Female) 


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(4) 
• 
CRN-F at Baseline (F0-F1, F2-F3) 
• 
NAS score at baseline (<6, ≥6) 
 


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5.2.2 Primary efficacy analysis 
 
5.2.2.1 
Primary analysis of the primary endpoint 
 
The primary efficacy endpoint is a binary variable (Responder / Non-responder) based on the 
change from baseline to Week 24 of the A Score (see section 4.5.4.1.6).  
 
The primary population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
Descriptive analysis 
 
The number (% with its 95% confidence interval) of responders and non-responders at Week 
24 will be summarized in a table using descriptive statistics by treatment group and diabetic 
status.  
The reason for non-response (No decrease of 2 points of SAF-A score, Worsening of CRN-F 
score, Both, No post-treatment biopsy available) will also be displayed.   
 
Evaluation of treatment effect (each dose versus placebo) 
 
Each treatment dose will be compared to placebo using a CMH test stratified on the diabetic 
status.  
 
In order to take into account multiplicity of tests, the ascending Hochberg procedure will be 
applied (see section 4.1.5 for details). The p-values of the 2 tests will be provided and will 
provide conclusions regarding the primary objective of the study met or not met. 
 
Corresponding CMH Odds ratio (OR) and adjusted-Relative Risk (RR) will be provided with 
their 95% confidence intervals, in the FAS for the two lanifibranor groups. 
The Breslow-Day test will be implemented for homogeneity of the odds ratios between diabetic 
and non-diabetic patients: 
- 
If the test is significant, then this means that the treatment effect has not the same 
magnitude in diabetic and non-diabetic patients (significant difference in OR in the 2 
populations) 
- 
If the test is not significant, then this means that the treatment effect has the same 
magnitude in diabetic and non-diabetic patients (no significant difference in OR in the 
2 populations).  
- 
Regardless the significance of the test, both OR and RR in diabetic and non-diabetic 
patients will be provided with their 95% confidence interval 
 
 
 
 


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5.2.2.2 
Sensitivity analyses 
 
Several sensitivity analyses will be performed on the primary criterion as detailed in table 
below. Each time, descriptive analysis and evaluation of treatment effect (each dose versus 
placebo) will be performed as detailed in section 5.2.2.1.  
To be confirmed. Indeed qualitative endpoint and not quantitative one => CMH and not MMRM …. 
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
Randomized set 
Randomized treatment assigned 
Primary imputation method 
PP 
Actual treatment received 
Observed cases under treatment 
EPP 
Actual treatment received 
Secondary imputation method 
FAS  
Actual treatment received 
Observed cases  
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
 
5.2.2.3 
Analysis by subgroups 
 
Descriptive analysis (number, % with its 95% confidence interval) will be performed in the 
FAS (primary imputation method) and among completers (Observed cases under treatment) as 
detailed in section 5.2.2.1 for the following subgroups of interest: 
 
- 
Biopsy length at baseline (≤ 8, >8 mm)  
- 
SAF-A score at baseline (A2-A3, A4) 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
- 
NAS score at baseline (<6, ≥6) 
- 
BMI at baseline (Obese, Non-obese) 
- 
Metabolic syndrome at baseline (Yes, No) 
- 
Insulin-resistance status at baseline (Yes, No) 
- 
Sex (Male, Female) 
 
 
5.2.2.4 Secondary analyses of the primary endpoint 
 
Dose-response relationship 
 
Moreover, the dose-response relationship will be assessed on the FAS (Primary imputation 
method and Observed cases under treatment), and on the PP (Observed cases under treatment) 
according to method detailed in section 4.1.5 (Cochran-Armitage test using PROC LOGISTIC 
with adjustment on diabetic status). 
 
Evaluation of dose effect (1200 mg vs. 800 mg) 
 
Lanifibranor 1200 mg will be compared to lanifibranor 800 mg using a CMH test stratified on 
the diabetic status. The same methodology as the one defined in the section 5.2.2.1 (paragraph 
‘Evaluation of treatment effect (each dose versus placebo)’) will be implemented. 
 


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Generalizability of the treatment effect: Evaluation of any “site” effect 
 
In order to explore any potential “site” effect on primary criterion, same analysis as those 
detailed in section 5.2.2.1 will be performed with a stratification on site (after regrouping as 
defined in section 4.1.7) instead of a stratification on diabetic status. Heterogeneity of results 
across sites will be tested through the Breslow-Day test (see section 4.1.7).  
 
The two strategies of site regrouping will be used to explore this potential “site” effect as 
detailed in section 4.1.7.  
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement. 
 
In a first time, analysis will be done considering all patients. Then it will be repeated on diabetic 
patients and on non-diabetic patients.  
 
Evaluation of treatment effect after adjustment on the relative change in weight from 
baseline  
 
In order to evaluate the treatment effect after adjustment on the relative change in weight from 
baseline, a LOGISTIC model will be run on the FAS - Observed Cases under treatment. For 
this model, treatment will be considered as a quantitative covariate (placebo, 800 mg and 
1200mg), diabetic status as a qualitative covariate (Presence, Absence) and weight variation as 
a quantitative effect. The p-value assessing the significant dose-response relationship at week 
24 will be provided based on this model, as well as the OR for a change of 2% in weight.  
 
 
 
 


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5.2.3 Secondary analyses 
 
5.2.3.1 NASH improvement 
 
The endpoint will be a binary variable (Improver / Non-improver) based on the change from 
baseline to Week 24 of the CRN NAS score (see section 4.5.4.1.7).  
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
- Descriptive analysis 
 
The number (% with its 95% confidence interval) of improvers and non-improvers at Week 24 
will be summarized in a table using descriptive statistics by treatment group and diabetic status.  
The reason for non-improvement (No decrease of 2 points of NAS score, Worsening of CRN-
F score, Both, No post-treatment biopsy available) will also be displayed.   
 
- Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
- Evaluation of dose effect (1200 mg vs. 800 mg) 
 
Lanifibranor 1200 mg will be compared to lanifibranor 800 mg using a CMH test stratified on 
the diabetic status. The same methodology as the one defined in the section 5.2.2.4 (paragraph 
‘Evaluation of dose effect (1200 mg vs. 800 mg)’) will be implemented. 
 
- Dose-response relationship 
 
The dose-response relationship will be assessed on the FAS (Primary imputation method and 
Observed cases under treatment), and on the PP (Observed cases under treatment) according to 
method detailed in section 4.1.5 (Cochran-Armitage test using PROC LOGISTIC with 
adjustment on diabetic status). 
 
 
Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis, evaluation of treatment effect (each dose versus placebo) and evaluation of dose effect 
will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
EPP 
Actual treatment received 
Secondary imputation method 


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* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
 
Analysis by subgroups 
 
Descriptive analysis (number, % with its 95% confidence interval) will be performed in the 
FAS (primary imputation method) and among completers (Observed cases under treatment) as 
detailed in section 5.2.2.1 for the following subgroups of interest: 
 
- 
NAS score at baseline (<6, ≥6) 
 
 
5.2.3.2 Resolution of NASH without worsening of fibrosis 
 
The endpoint will be a binary variable (responder / non responder) based on the CRN-I and 
CRN-B scores at Week 24 and the change in CRN-F score from Baseline to Week 24 (see 
section 4.5.4.1.8).  
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
- Descriptive analysis 
 
The number (% with its 95% confidence interval) of responders and non-responders at Week 
24 will be summarized in a table using descriptive statistics by treatment group and diabetic 
status.  
The reason for non-response (CRN-Inflammation > 1, ± CRN-Ballooning > 0, ± Worsening of 
CRN-F score, No post-treatment biopsy available) will also be displayed.   
 
- Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
- Evaluation of dose effect (1200 mg vs. 800 mg) 
 
Lanifibranor 1200 mg will be compared to lanifibranor 800 mg using a CMH test stratified on 
the diabetic status. The same methodology as the one defined in the section 5.2.2.4 (paragraph 
‘Evaluation of dose effect (1200 mg vs. 800 mg)’) will be implemented. 
 
- Dose-response relationship 
 
Moreover, the dose-response relationship will be assessed on the FAS (Primary imputation 
method and Observed cases under treatment), and on the PP (Observed cases under treatment) 
according to method detailed in section 4.1.5 (Cochran-Armitage test using PROC LOGISTIC 
with adjustment on diabetic status). 
 
 


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Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis, evaluation of treatment effect (each dose versus placebo), evaluation of dose effect 
(1200 mg vs. 800 mg) will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
EPP 
Actual treatment received 
Secondary imputation method 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
 
Analysis by subgroups 
 
Descriptive analysis (number, % with its 95% confidence interval) will be performed in the 
FAS (primary imputation method) and among completers (Observed cases under treatment) as 
detailed in section 5.2.2.1 for the following subgroups of interest: 
 
- 
Biopsy length at baseline (≤ 8, >8 mm)  
- 
SAF-A score at baseline (A2-A3, A4) 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
- 
NAS score at baseline (<6, ≥6) 
- 
BMI at baseline (Obese, Non-obese) 
- 
Metabolic syndrome at baseline (Yes, No) 
- 
Insulin-resistance status at baseline (Yes, No) 
- 
By site group No. 1 (Bulgaria, all other countries) 
- 
By site group No. 2 (3 or less patients randomised and treated, from 4 to 9 patients 
randomised and treated, 10 or more patients randomised and treated) 
- 
Sex (Male, Female) 
 
 
5.2.3.3 Improvement of fibrosis by at least 1 stage with no worsening of NASH 
 
The endpoints will be a binary variable (responder / non responder) based on the change from 
baseline to Week 24 of the CRN-F score and the worsening of NASH (see section 4.5.4.1.9). 
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
- Descriptive analysis 
 
The number (% with its 95% confidence interval) of responders and non-responders at Week 
24 will be summarized in a table using descriptive statistics by treatment group and diabetic 
status.  


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The reason for non-response (Worsening of CRN-S score, ± Worsening of CRN-I score, ± 
Worsening of CRN-B score, ± No improvement of CRN-F score, No post-treatment biopsy 
available) will also be displayed.   
 
- Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
- Evaluation of dose effect (1200 mg vs. 800 mg) 
 
Lanifibranor 1200 mg will be compared to lanifibranor 800 mg using a CMH test stratified on 
the diabetic status. The same methodology as the one defined in the section 5.2.2.4 (paragraph 
‘Evaluation of dose effect (1200 mg vs. 800 mg)’) will be implemented. 
 
- Dose-response relationship 
 
Moreover, the dose-response relationship will be assessed on the FAS (Primary imputation 
method and Observed cases under treatment), and on the PP (Observed cases under treatment) 
according to method detailed in section 4.1.5 (Cochran-Armitage test using PROC LOGISTIC 
with adjustment on diabetic status). 
 
 
 
 


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Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis, evaluation of treatment effect (each dose versus placebo), evaluation of dose effect 
(1200 mg vs. 800 mg) will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
EPP 
Actual treatment received 
Secondary imputation method 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
Analysis by subgroups 
 
Descriptive analysis (number, % with its 95% confidence interval) will be performed in the 
FAS (primary imputation method) and among completers (Observed cases under treatment) as 
detailed in section 5.2.2.1 for the following subgroups of interest: 
 
- 
Biopsy length at baseline (≤ 8, >8 mm)  
- 
SAF-A score at baseline (A2-A3, A4) 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
- 
NAS score at baseline (<6, ≥6) 
- 
BMI at baseline (Obese, Non-obese) 
- 
Metabolic syndrome at baseline (Yes, No) 
- 
Insulin-resistance status at baseline (Yes, No) 
- 
By site group No. 1 (Bulgaria, all other countries) 
- 
By site group No. 2 (3 or less patients randomised and treated, from 4 to 9 patients 
randomised and treated, 10 or more patients randomised and treated) 
- 
Sex (Male, Female) 
 
 


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5.2.3.4 Resolution of NASH and Improvement of fibrosis by at least 1 stage 
 
The endpoint will be a binary variable (responder / non responder) based on the CRN-I and 
CRN-B scores at Week 24 and the change in CRN-F score from Baseline to Week 24 (see 
section 4.5.4.1.10).  
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
- Descriptive analysis 
 
The number (% with its 95% confidence interval) of responders and non-responders at Week 
24 will be summarized in a table using descriptive statistics by treatment group and diabetic 
status.  
The reason for non-response (CRN-I score not equal to {0, 1}, ± CRN-B score not equal to 0, 
± No improvement of CRN-F score, No post-treatment biopsy available) will also be displayed.   
 
- Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
- Evaluation of dose effect (1200 mg vs. 800 mg) 
 
Lanifibranor 1200 mg will be compared to lanifibranor 800 mg using a CMH test stratified on 
the diabetic status. The same methodology as the one defined in the section 5.2.2.4 (paragraph 
‘Evaluation of dose effect (1200 mg vs. 800 mg)’) will be implemented. 
 
- Dose-response relationship 
 
Moreover, the dose-response relationship will be assessed on the FAS (Primary imputation 
method and Observed cases under treatment), and on the PP (Observed cases under treatment) 
according to method detailed in section 4.1.5 (Cochran-Armitage test using PROC LOGISTIC 
with adjustment on diabetic status). 
 
Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis, evaluation of treatment effect treatment effect (each dose versus placebo), evaluation 
of dose effect (1200 mg vs. 800 mg) will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
EPP 
Actual treatment received 
Secondary imputation method 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 


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Analysis by subgroups 
 
Descriptive analysis (number, % with its 95% confidence interval) will be performed in the 
FAS (primary imputation method) and among completers (Observed cases under treatment) as 
detailed in section 5.2.2.1 for the following subgroups of interest: 
 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
- 
NAS score at baseline (<6, ≥6) 
 
 
5.2.3.5 Resolution of NASH without worsening of fibrosis and NASH improvement 
 
The endpoint will be a binary variable (responder / non responder) based on the CRN-I and 
CRN-B scores at Week 24, the change in CRN-F score and CRN NAS score from Baseline to 
Week 24 (see section 4.5.4.1.11).  
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
- Descriptive analysis 
 
The number (% with its 95% confidence interval) of responders and non-responders at Week 
24 will be summarized in a table using descriptive statistics by treatment group and diabetic 
status.  
The reason for non-response (CRN-I score not equal to {0, 1}, ± CRN-B score not equal to 0, 
± Worsening of CRN-F score, ± No decrease of 2 points of NAS score, No post-treatment 
biopsy available) will also be displayed.   
 
- Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
- Evaluation of dose effect (1200 mg vs. 800 mg) 
 
Lanifibranor 1200 mg will be compared to lanifibranor 800 mg using a CMH test stratified on 
the diabetic status. The same methodology as the one defined in the section 5.2.2.4 (paragraph 
‘Evaluation of dose effect (1200 mg vs. 800 mg)’) will be implemented. 
 
Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis, evaluation of treatment effect treatment effect (each dose versus placebo), evaluation 
of dose effect (1200 mg vs. 800 mg) will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 


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PP 
Actual treatment received 
Observed cases under treatment 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
 
Analysis by subgroups 
 
None 
 
 
5.2.3.6 Change in components Steatosis (CRN-S), Activity (SAF-A), Inflammation (CRN-I) 
and Ballooning (CRN-B) 
 
5.2.3.6.1 Improvement  
 
The endpoints are the following components: CRN-S, CRN-I and CRN-B scores. For each 
component, the following variable will be considered based on the change from baseline to 
Week 24:  
- Improvement of at least 1 point change of the component (Yes, No)  
 
Descriptive analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
The number (% with its 95%CI) of improvement (Yes, No) at Week 24 will be summarized in 
a table using descriptive statistics by treatment group and diabetic status.    
 
Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
 
5.2.3.6.2 Change in components 
 
For each component (CRN-S, SAF-A, CRN-I and CRN-B scores), the following variables will 
be considered based on the change from baseline to Week 24 of:   
- Absolute change of the component (quantitative variables)  


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- Change in the component (…Improvement of 2 points, Improvement of 1 point, No 
change, Worsening of 1 point, Worsening of 2 points…) 
- Change in the component (Improvement of at least 1 point/No change/Worsening of at 
least 1 point) 
 
Descriptive analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. Only the observed 
cases under treatment will be analysed (see section 4.1.6.3).  
 
Endpoint will be summarized at Week 24 in a table using descriptive statistics by treatment 
group and diabetic status.  
 
Sensitivity analysis 
 
A single sensitivity analysis will be performed as detailed in table below. Each time, descriptive 
analysis will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
PP 
Actual treatment received 
Observed cases under treatment 
 
 
5.2.3.7 Change in component Fibrosis of CRN score and modified Fibrosis Ishak 
 
5.2.3.7.1 Improvement or No worsening 
 
The endpoints are the component CRN-F score and the modified Fibrosis Ishak score (modified 
ISHAK-F). For each score, the following variables will be considered based on the change from 
baseline to Week 24:  
- Improvement of at least 1 point of the fibrosis score (Yes, No)  
- No worsening of the fibrosis score (Yes, No) 
 
Descriptive analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
The number (% with its 95% CI) of improvement (Yes, No) and no worsening (Yes, No) at 
Week 24 will be summarized in a table using descriptive statistics by treatment group and 
diabetic status.    
 
Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis will be performed as detailed above for main analysis.  


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Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 
 
 
Analysis by subgroups 
 
Descriptive analysis will be performed in the FAS (primary imputation method) and among 
completers (Observed cases under treatment) for the following subgroups of interest: 
 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
 


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5.2.3.7.2 Change in component 
 
For each fibrosis score (CRN-F and modified ISHAK-F scores), the following variables will be 
considered based on the change from baseline to Week 24 of:   
- Absolute change of the score (quantitative variables)  
- Change in the score (…Improvement of 2 points, Improvement of 1 point, No change, 
Worsening of 1 point, Worsening of 2 points…) 
- Change in the score (Improvement of at least 1 point /No change/Worsening of at least 
1 point) 
 
Descriptive analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. Only the observed 
cases under treatment will be analysed (see section 4.1.6.3).  
 
Endpoint will be summarized at Week 24 in a table using descriptive statistics by treatment 
group and diabetic status.  
 
Sensitivity analysis 
 
A single sensitivity analysis will be performed as detailed in table below. Each time, descriptive 
analysis will be performed as detailed above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
PP 
Actual treatment received 
Observed cases under treatment 
 
Analysis by subgroups 
 
Descriptive analysis regarding CRN-F will be performed in the FAS (Observed cases under 
treatment) for the following subgroups of interest: 
 
- 
CRN-F score at baseline (F0-F1, F2-F3) 
 
 


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5.2.3.8 Glucose metabolism 
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. Only the observed 
cases under treatment will be analysed (see section 4.1.6.3). 
 
Only fasting results will be considered for fasting glucose, insulin, C-peptid and HOMA index. 
HbA1c and fructosamide results will be considered regardless of the fasting status. 
 
- Descriptive analysis 
 
Fasting glucose and HbA1c assessed at Screening, Baseline, Week 4, Week 14, Week 24 and 
Week 28, as well as insulin, C-peptid, fructosamide and HOMA index assessed at Week 0 and 
Week 24, will be described over time  using descriptive statistics by treatment group and 
diabetic status, in terms of: 
- Raw values 
- Absolute change from baseline 
The 95% CI of the mean will also be provided. 
- Status over time (Normal-Normal, Normal-Abnormal, Abnormal-Normal, Abnormal-
Abnormal)  
The 2 timepoints prior to first intake will have to be analysed: screening and baseline. 
 
One graph will also be provided describing the raw values (with 95% CI) by treatment group 
over time (including screening values) 
 
The HOMA index will also be described qualitatively over time using descriptive statistics by 
treatment group and diabetic status (HOMA<3, ≥3). 
 
- Absolute changes in HbA1c value will be described qualitatively over time using 
descriptive statistics by treatment group and diabetic status:  
o Decrease of HbA1c (Decrease of 1%, No change (Change within ]-1% ; 1%[), 
Increase ≥ 1%). 
o Decrease of HbA1c (Decrease ≥ 0.5%, No change (Change within ]-0.5% ; 
0.5%[), Increase ≥ 0.5%) 
 
- Evaluation of treatment effect (each dose versus placebo) 
 
For fasting glucose, HbA1c, insulin and HOMA index, in order to evaluate each treatment dose 
versus placebo at week 24, a MMRM will be performed as detailed in section 4.1.5. 
In order to take into account multiplicity of tests, the ascending Hochberg procedure will be 
applied (see section 4.1.5 for details).  
 
- Time course of the response of each treatment group 
 
For fasting glucose and HbA1c, in order to evaluate the time course of the response of each 
treatment group, a MMRM will be performed as detailed in section 4.1.5. 
In order to take into account multiplicity of tests, the ascending Hochberg procedure will be 
applied at each time point (see section 4.1.5 for details).  
  


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Sensitivity analysis 
None 
 
Analysis by subgroups (descriptive analysis only) 
 
- 
By diabetic status (Yes, No) for fasting glucose, insulin, C-peptid, HOMA index,  
fructosamide and HbA1c 
- 
By HbA1c at baseline (<=6.5%, >6.5%) for HbA1c 
 
 
5.2.3.9 Liver enzymes 
 
The following table describes for each parameter the collection time and the type of analyses 
to be done. 
 
Parameter 
Collection time 
Main analyses 
(see section 5.2.3.8 describing 
the methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
ALT 
Screening, 
Baseline, weeks 
4, 14, 24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response of 
each treatment group 
None 
By diabetic 
status (Yes, 
No) 
AST 
Screening, 
Baseline, weeks 
4, 14, 24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response of 
each treatment group 
None 
By diabetic 
status (Yes, 
No) 
GGT 
Screening, 
Baseline, weeks 
4, 14, 24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response of 
each treatment group 
None 
By diabetic 
status (Yes, 
No) 
Alkaline 
Phosphatase 
Screening, 
Baseline, weeks 
4, 14, 24 and 28 
Descriptive analysis 
None 
By diabetic 
status (Yes, 
No) 
Total 
Bilirubin 
Screening, 
Baseline, weeks 
4, 14, 24 and 28 
Descriptive analysis 
None 
By diabetic 
status (Yes, 
No) 
 
 
 
 
 


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5.2.3.10 Plasma lipids levels  
 
The following table describes for each parameter the collection time and the type of analyses 
to be done. 
 
Parameter 
Collection 
time 
Main analyses 
(see section 5.2.3.8 
describing the 
methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
Total 
Cholesterol 
Screening, 
Baseline, 
weeks 4, 14, 
24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response 
of each treatment group 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
HDL-C 
Screening, 
Baseline, 
weeks 4, 14, 
24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response 
of each treatment group 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
LDL-C 
Screening, 
Baseline, 
weeks 4, 14, 
24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response 
of each treatment group 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
Triglycerides 
Screening, 
Baseline, 
weeks 4, 14, 
24 and 28 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
Time course of the response 
of each treatment group 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
Apo A1 
Baseline, 
week 24  
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
FFA 
Baseline, 
week 24 
Descriptive analysis 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
Adiponectin 
Baseline, 
week 24 
Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
Leptin 
Baseline, 
week 24 
Descriptive analysis 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
APO B 
Baseline, 
week 24 
Descriptive analysis 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
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Parameter 
Collection 
time 
Main analyses 
(see section 5.2.3.8 
describing the 
methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
APO C3 
Baseline, 
week 24 
Descriptive analysis 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
FGF21 
Baseline, 
week 24 
Descriptive analysis 
None 
By diabetic status 
(Yes, No) 
By 
Statins 
at 
baseline (Yes, No) 
 
Only fasting results will be considered for analyses. 
For adiponectin, folds being defined as the value at week 24 divided by baseline value will also 
be presented in the descriptive analysis. 
  
 
 


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5.2.3.11 Efficacy inflammatory markers 
 
The following table describes for each parameter the collection time and the type of analyses 
to be done. 
 
Parameter 
Collection time 
Main analyses 
(see section 5.2.3.8 
describing the 
methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
Fibrinogen 
Baseline, week 24 Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
None 
None 
Hs-CRP 
Baseline, week 24 Descriptive analysis 
Treatment effect (each dose 
versus placebo) 
None 
None 
alpha2 
macroglobulin 
Baseline, week 24 Descriptive analysis 
None 
None 
Haptoglobin 
Baseline, week 24 Descriptive analysis 
None 
None 
IL-13 
Baseline, week 24 Descriptive analysis 
None 
None 
IL-17a 
Baseline, week 24 Descriptive analysis 
None 
None 
IL-6 
Baseline, week 24 Descriptive analysis 
None 
None 
IL-1b 
Baseline, week 24 Descriptive analysis 
None 
None 
TNF-a 
Baseline, week 24 Descriptive analysis 
None 
None 
INFg 
Baseline, week 24 Descriptive analysis 
None 
None 
 
 
 
 


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5.2.3.12 Efficacy fibrosis markers 
 
The following table describes for each parameter the collection time and the type of analyses 
to be done. 
 
Parameter 
Collection time 
Main analyses 
(see section 5.2.3.8 
describing the 
methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
TIMP-1 
Baseline, week 24 
Descriptive analysis 
None 
None 
TIMP-2 
Baseline, week 24 
Descriptive analysis 
None 
None 
Hyaluronic acid 
Baseline, week 24 
Descriptive analysis 
None 
None 
P3NP 
Baseline, week 24 
Descriptive analysis 
None 
None 
NFS 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
FIB-4 score 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
ELF score 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
MACK-3 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
FIBC3 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
ABC3D 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
Cytokeratin M30 
Baseline, week 24 
Descriptive analysis 
None 
None 
Cytokeratin M65 
Baseline, week 24 
Descriptive analysis 
None 
None 
MMP2 
Baseline, week 24 
Descriptive analysis 
None 
None 
MMP9 
Baseline, week 24 
Descriptive analysis 
None 
None 
Pro-C3 
Baseline, week 24 
Descriptive analysis 
Treatment effect (each 
dose versus placebo) 
None 
None 
 
The following variables will also be described qualitatively over time using descriptive 
statistics by treatment group and diabetic status  
- ELF score (No to mild fibrosis, moderate fibrosis, severe fibrosis, cirrhosis) 
- NFS (Low probability of fibrosis F3-F4, Intermediate, High probability of fibrosis F3-
F4) 
- FIB-4 score (Low probability of fibrosis F3-F4, Intermediate, High probability of 
fibrosis F3-F4) 
- MACK-3 score (No fibrosis, Fibrosis undefinable (grey zone), Fibrosis) 
Moreover, as an exploratory analysis, the ELF score in class, the NFS in class and the FIB-4 
score in class will be cross-tabulated with the CRN-F score (F0-F1, F2-F3): at baseline and then 


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at Week 24, regardless of treatment group. Similarly, the MACK-3 score in class will be cross-
tabulated with the CRN-F score (F0, F1, F2, F3). 
 
The ProC3, FIBC3 and ABC3D values will be described in each modality of the CRN-F score 
(F0-F1, F2-F3): at baseline and then at Week 24, regardless of treatment group. 
 
 
5.2.3.13 Efficacy chemistry markers 
 
The following table describes for each parameter the collection time and the type of analyses 
to be done. 
 
Parameter 
Collection time 
Main analyses 
(see section 5.2.3.8 
describing the 
methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
Plasma Iron Screening, week 24 
Descriptive analysis 
None 
None 
Transferrin 
Screening, week 24 
Descriptive analysis 
None 
None 
Ferritin 
Screening, week 24 
Descriptive analysis 
None 
None 
 
 
 


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5.2.3.14 Improvement of ISHAK fibrosis by at least 2 stages with no worsening of NASH 
 
The endpoints will be a binary variable (responder / non responder) based on the change from 
baseline to Week 24 of the ISHAK-F score and the worsening of NASH (see section 4.5.4.1.12). 
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. The primary 
imputation method described in section 4.1.6.3 will be used for missing data replacement.  
 
- Descriptive analysis 
 
The number (% with its 95% confidence interval) of responders and non-responders at Week 
24 will be summarized in a table using descriptive statistics by treatment group and diabetic 
status.  
The reason for non-response (Worsening of CRN-S score, ± Worsening of CRN-I score, ± 
Worsening of CRN-B score, ± No improvement of 2 stages in ISHAK-F score, No post-
treatment biopsy available) will also be displayed.   
 
- Evaluation of treatment effect (each dose versus placebo) 
 
The same methodology as the one defined in the section 5.2.2.1 (paragraph ‘Evaluation of 
treatment effect (each dose versus placebo)’) will be implemented. 
 
- Dose-response relationship 
 
Moreover, the dose-response relationship will be assessed on the FAS (Primary imputation 
method and Observed cases under treatment), and on the PP (Observed cases under treatment) 
according to method detailed in section 4.1.5 (Cochran-Armitage test using PROC LOGISTIC 
with adjustment on diabetic status). 
 
Sensitivity analyses 
 
Several sensitivity analyses will be performed as detailed in table below. Each time, descriptive 
analysis, evaluation of treatment effect (each dose versus placebo) will be performed as detailed 
above for main analysis.  
 
Analysis population 
Treatment group 
Missing data replacement 
FAS  
Actual treatment received 
Observed cases under treatment* 
PP 
Actual treatment received 
Observed cases under treatment 
* This analysis corresponds to analyses on completers (biopsy at week 24 performed, within maximum 14 days 
after last intake). 


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5.3 
Safety data  
 
5.3.1 Extent of exposure 
 
The following parameters will be summarized in a table using descriptive statistics by treatment 
group in the safety set of patients: 
- 
Treatment prematurely discontinued during study (Yes, No) 
- 
Treatment duration (weeks) 
- 
Overall persistence (%) 
- 
Overall compliance at time of biopsy at week 24 (%) 
- 
Overall compliance at time of biopsy at week 24 (%) based on lanifibranor bottles 
- 
Compliance (%) at each visit 
 
 
5.3.2 Display of adverse events 
 
5.3.2.1 
Overall summary of Treatment Emergent Adverse Events (TEAEs) 
 
The following summary statistics will be given in the safety set of patients by treatment group 
(Lanifibranor 800mg, lanifibranor 1200mg, lanifibranor all, placebo): 
 
- 
Number (%) of patients with at least one TEAE 
- 
Number (%) of patients with at least one TEAE related to treatment 
- 
Number (%) of patients with at least one TESAE 
- 
Number (%) of patients with at least one TESAE related to treatment 
 
- 
Number (%) of patients with a fatal TESAE 
- 
Number (%) of patients with a fatal TESAE related to treatment 
 
- 
Number (%) of patients with at least one mild TEAE 
- 
Number (%) of patients with at least one moderate TEAE 
- 
Number (%) of patients with at least one severe TEAE 
 
- 
Number (%) of patients with at least one severe TEAE related to treatment 
- 
Number (%) of patients with at least one severe TESAE 
- 
Number (%) of patients with at least one severe TESAE related to treatment 
 
- 
Number (%) of patients with at least one TEAE leading to treatment permanent 
discontinuation 
- 
Number (%) of patients with at least one TEAE leading to treatment permanent 
discontinuation related to treatment 
 
Corresponding number of events will also be provided for each type of AEs. 
 
 
 


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5.3.2.2 
Overall Analysis of Treatment Emergent Adverse Events (TEAEs) 
 
The number (%) of patients with at least one TEAE (and the corresponding number of events) 
will be described by SOC and PT by treatment group in the safety set of patients. In case a 
same patient presented the same AE (i.e. same AE as defined according to SOC and PT) several 
times during the study, only one occurrence per patient will be reported, but the total number 
of events will be given.  
 
Same tables as this one will also be produced for: 
- 
TEAE related to treatment 
- 
TESAE 
- 
TESAE related to treatment 
- 
Fatal TESAE 
- 
Severe TEAE 
- 
Severe TEAE related to treatment 
- 
Severe TESAE 
- 
Severe TESAE related to treatment 
- 
TEAE leading to treatment permanent discontinuation 
- 
TEAE leading to treatment permanent discontinuation related to treatment 
 
 
5.3.2.3 
Analysis of Non-Treatment Emergent Adverse Events (non-TEAEs) 
 
For Non-TEAEs, only a listing will be edited in the safety set of patients. 
 
 
5.3.2.4 
Analysis of Post-Treatment Adverse Events (PTAEs) 
 
For PTEAEs, only a listing will be edited in the safety set of patients. 
 
 
5.3.2.5 
Analysis of Adverse Events in screen failure patients 
 
A listing of all AEs experienced in screen failure patients will be edited. 
 
5.3.3 Other safety analysis 
 
5.3.3.1 Specific cardiac inflammatory safety: NT-pro-BNP 
 
The population of analysis will be the Safety Set as described in section 4.3.3. Only the 
observed cases under treatment will be analysed (see section 4.1.6.3).  
 
The NT-pro-BNP is collected at baseline and week 24. A listing of abnormal values at Baseline 
and/or Week 24 will be provided including absolute and relative changes from baseline. 
 
 
 


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5.3.3.2 Bone remodelling 
 
The following table describes for each parameter the collection time and the type of analyses 
to be done. 
 
Parameter 
Collection time 
Main analyses 
(see section 5.2.3.8 
describing the methodology) 
Sensitivity 
analyses 
Subgroup 
analyses 
B-Crosslaps 
Baseline, week 24 Descriptive analysis 
None 
By gender 
Osteocalcin 
Baseline, week 24 Descriptive analysis 
None 
By gender 
 
 
5.3.3.3 Laboratory tests for safety assessment 
 
The following parameters will be considered for the analyses: 
- Haematology 
o RBC count (10^12/L), 
o WBC count (10^9/L), 
o WBC differential: Neutrophil, Lymphocyte, Monocyte, Eosinophil, Basophil 
(10^9/L),  
o Reticulocytes (10^9/L), 
o Haemoglobin (g/L), 
o Haematocrit (L/L), 
o Platelet count (10^9/L), 
o Erythrocytes Mean Corpuscular Volume (MCV) (fL),  
o Mean Corpuscular Haemoglobin Concentration (MCHC) (g/L) 
- Chemistry 
o Creatinine (µmol/L), 
o Urea (mmol urea/L), 
o Albumin (g/L), 
o Creatine PhosphoKinase (UI/L), 
o eGFR (mL/min/1.73m²)  
- 
Liver/coagulation 
o INR 
 
Main analysis 
 
The population of analysis will be the Safety Set as described in section 4.3.4. Only the 
observed cases under treatment will be analysed (see section 4.1.6.3).  
 
- Descriptive analysis 
 
Each parameter will be described at each study visit using descriptive statistics by treatment 
group in the safety set of patients, in terms of: 
- Raw values 
- Absolute change from Baseline 
- Status over time (Normal-Normal, Normal-Abnormal, Abnormal-Normal, Abnormal-
Abnormal)  


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Then, for each parameter, will be provided a graph reporting the mean (95% CI) of the 
parameter by visit and treatment group.  
 
Sensitivity analysis 
None 
 
Analysis by subgroups 
None 
 
 
5.3.3.4 Anthropometric and vital signs 
 
The following vital signs parameters will be summarized in a table using descriptive statistics 
by treatment group at each study visit (from baseline to week 28) in the safety set of patients: 
- 
Weight (kg), 
- 
Systolic Blood Pressure (mmHg), 
- 
Diastolic Blood Pressure (mmHg). 
  
The corresponding relative changes from baseline will also be described by treatment group at 
each study visit.  
 
Additionally, will be presented at each study visit the number (%) of patients presenting a 
relative change from baseline in weight (Decrease of ≥ 10%, Decrease from ≥ 5% to < 10%, 
No change (Change within]-5% ; 5%[), Increase from ≥ 5% to < 10%, Increase of ≥ 10%). A 
graph reporting the mean (95% CI) weight by visit and treatment group will be provided.  
 
 
 
5.3.3.5 Electrocardiogram (ECG) 
 
The following parameters will be considered for the analyses of ECG: 
- 
Status over time (based on the conclusion of the central reader): 
o Normal or Abnormal NCS - Normal or Abnormal NCS 
o Normal or Abnormal NCS - Abnormal CS  
o Abnormal CS – Normal or Abnormal NCS 
o Abnormal CS - Abnormal CS 
- 
QT duration corrected according to Fridericia formula (QTcF) (ms) 
- 
QTcF > 450 ms (Yes, No) 
- 
QTcF > 480 ms (Yes, No) 
- 
QTcF > 500 ms (Yes, No) 
- 
Absolute change from baseline in QTcF (ms) 
- 
Absolute change from baseline ≥ 60 ms (Yes, No) 
- 
Absolute change from baseline ≥ 30 ms (Yes, No) 
- 
HR (beats/min) 
- 
HR in categories (<40 beats/min, ≥40 and ≤ 120 beats/min, >120 beats/min)  
- 
Relative change in HR from baseline (≤ 25 %, >25%)  


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Each parameter will be described at each study visit using descriptive statistics by treatment 
group overall and by gender in the safety set of patients. 
 
Then, for QTcF and HR, will be provided a graph reporting the mean (+/- 95% CI) of the 
parameter by visit and treatment group.  
 
A listing of abnormal CS interpretation at Baseline and/or over time will be provided. 


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5.4 
Quality of Life  
 
The endpoints will be the 10 sub-scores of the SF-36 and the global score of FFS (see sections 
4.5.5.1 and 4.5.5.2).   
 
Main analysis 
 
The population of analysis will be the FAS as described in section 4.3.3. Only the observed 
cases under treatment will be analysed (see section 4.1.6.3).  
 
- Descriptive analysis 
 
Each score/sub-score will be described over time (Baseline and Week 24) using descriptive 
statistics by treatment group, in terms of: 
- Raw values 
- Absolute change from baseline 
 
One graph will also be provided describing the raw values (with 95%CI) by treatment group 
over time. 
 
 
 
 
 
 
 
 
 
 


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5.5 
Exploratory data  
 
5.5.1 Liver biopsy 
 
The following variables will be described by treatment and by diabetic status, for the biopsies 
at week 24: 
 
- 
CRN-S score (S0, S1, S2, S3) 
- 
CRN-S (quantitative) 
- 
CRN-I score (Grades 0, 1, 2) 
- 
CRN-I (quantitative) 
- 
CRN-B score (Grades 0, 1, 2) 
- 
CRN-B (quantitative) 
- 
CRN NAS score (from 0 to 8) 
- 
CRN NAS score (quantitative) 
- 
SAF-I score (Grades 0, 1, 2) 
- 
SAF-I (quantitative) 
- 
SAF-A score (A2, A3, A4) 
- 
SAF-A score (A2-A3, A4) 
- 
SAF-A (quantitative) 
- 
CRN-F score (F0, F1, F2, F3) 
- 
CRN-F score (F0-F1, F2-F3) 
- 
CRN-F score (quantitative) 
- 
Fibrosis Stage (modified Ishak) (Stages 0, 1, 2, 3, 4, 5, 6) 
- 
Fibrosis Stage (modified Ishak) (quantitative) 
- 
Biopsy length (mm) 
- 
Biopsy length (≤ 8, >8 mm) 
- 
Iron overload intensity (Absent, mild, moderate, severe) 
- 
Iron overload location (None, Macrophages, Hepatocytes, Both) 
 
All other information collected in the biopsy form will be listed individually in Listings 16.2. 
 
 
5.5.2 Fibroscan 
 
The following variables will be described by treatment:  
- 
TE / Stiffness (kPa) 
- 
CAP (dB.m-1) 
- 
Probe used (M, XL) 
- 
Probe used at Screening and Visit 3 (M-M, M-XL, XL-M, XL-XL) 
If the same probes were used (ie M-M or XL-XL): 
- 
Absolute change in TE / Stiffness (kPa) 
- 
Absolute change in CAP (dB.m-1) 
 
All other information regarding the Fibroscan will be listed individually in Listings 16.2. 
 
 
 
 


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5.5.3 Alcohol consumption 
 
The following parameters will be summarized in a table using descriptive statistics by treatment 
group at each study visit in the safety set of patients for males and then females: 
- 
Alcohol consumption since last visit (Yes, No) 
o If consumption, drinks/day (quali) 
- 
Drinks/day (quali) (this value will be defined as 0 for patient with no alcohol 
consumption) 
 
 
5.5.4 Immunohistochemistry (semi-quantitative score of ballooning and stellate cell 
activation) 
 
If deemed necessary at the time of the availability of the study results, complementary 
immunohistochemistry analyses could be performed within the year after the end of the study, 
and specific analyses analysis considered relevant in the scope of the study to understand the 
safety and efficacy of lanifibranor in patients with NASH could be performed. A separate 
dedicated SAP will cover this endpoint. 
 
 
5.5.5 Pharmacokinetic data 
 
The following variables will be summarized in a table using descriptive statistics by lanifibranor 
group at each study visit (Visit 1 and Visit 3) in the safety set of patients, overall, by gender 
(Male, Female), by BMI at baseline (Obese, Non-obese) and by age in class (<65, ≥65 years 
old): 
- 
Trough values for lanifibranor and its 3 metabolites 
- 
Metabolites ratio defined as the value of the metabolite/value of parent (Lanifibranor) 
for the 3 metabolites. If the value of parent is 0 or BLQ, then the ratio will be missing. 
 
Four box plots for lanifibranor and its 3 metabolites displaying the trough values will be edited 
for each lanifibranor group overall. 
 
Some values may be aberrant. In this purpose, only values collected before the treatment intake 
will be considered in the analyses. BLQ (Below Limit of Quantification) values will be 
considered as 0.  
 


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6 
Tables, Listings and Graphs (TLG) 
 
See appended document: 
INVENTIVA_NATIVE_SAP_Mock_Up_TFLs_Version1.0_20200513.pdf 
 
 
7 
Template of tables, listings and graphs 
 
See appended document: 
INVENTIVA_NATIVE_SAP_Mock_Up_TFLs_Version1.0_20200513.pdf 
 
 
8 
Appendix 1 - Correspondence between patient number and country 
 
Country number: first two digits of 
patient number 
Country 
00 
Belgium 
01 
Italy 
02 
France 
03 
UK 
04 
Switzerland 
05 
Spain 
06 
Portugal 
07 
Poland 
08 
Germany 
09 
Czech Republic 
10 
Austria 
11 
Netherlands 
12 
Australia 
13 
Canada 
14 
Mauritius 
15 
Bulgaria 
16 
United States 
17 
Slovenia 


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9 
Appendix 2 - Contents of statistical deliverables 
 
See appended document: INVENTIVA_NATIVE_SAP_Mock_Up_TFLs 
 
 
10 Appendix 3 – Strategy for analysis QC 
 
 
See appended document: INVENTIVA_NATIVE_SAP_Mock_Up_TFLs 
 
 
11 References 
 
Reference 1 
EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholoc 
fatty liver disease, Clinical Practice Guidelines, Journal of hepatology 2016 vol.64 1388-
1402 
Reference 2 
P. Angulo, J.M. Hui, G. Marchesini, E. Bugianesi, J. George, G.C. Farrell, et al. The 
NAFLD fibrosis score: a non-invasive system that identifies liver fibrosis in patients with 
NAFLD. Hepatology, 45 (2007), pp. 846-854 
Reference 3 
Sterling, R. K., Lissen, E., Clumeck, N., Sola, R., Correa, M. C., Montaner, J., S. 
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M. (2006), Development of a simple noninvasive index to predict significant fibrosis in 
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Reference 4 
Ralf Lichtinghagen, Daniel Pietsch, Heike Bantel, Michael P. Manns, Korbinian Brand, 
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factors and proposed cut-off values, EASL European Association for the Study of the 
Liver, Journal of Hepatology 
Reference 5 
Hui Liu, Merck Research Labs, Merck & Co., Inc, Rahway, NJ, Cochran-Armitage Trend 
Test Using SAS 
Reference 6 
J. Boursier & all, Screening for therapeutic trials and treatment indication in clinical 
practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH, Aliment 
Pharmacol Ther. 2018 May; 47(10):1387-139 


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Reference 7 
Gradisar M, Lack L, Richards H, et al. The Flinders Fatigue Scale: preliminary 
psychometric properties and clinical sensitivity of a new scale for measuring daytime 
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Reference 8 
Boyle M. and all, Performance of the PRO-C3 collagen neo-epitope biomarker in non-
alcoholic fatty liver disease, JHEP Rep. 2019 Jul 4;1(3):188-198