Efficacy, Safety and Mechanism of Action of Lanifibranor (IVA337) in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
Phase: PHASE2
Conditions: Nonalcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes (T2DM)
Sponsor: University of Florida

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STUDY PROTOCOL 
 
NCT03459079 
Protocol identification: lanifibranor/2018 
IRB number: 
Version 2.5 – February 6, 2022 
 
Study title 
Efficacy, Safety and Mechanism of Action of Lanifibranor 
(IVA337) in Patients with Type 2 Diabetes (T2DM) and 
Nonalcoholic Fatty Liver Disease (NAFLD) 
Investigational medicinal product: IVA337 (lanifibranor) 
 
Development Phase: II. Investigator Initiated study 
Study initiation date: Q1 2018 
Study completion date (expected): Q2 2020 
 
Principal Investigator: Kenneth Cusi, M.D., F.A.C.P., F.A.C.E 
Professor of Medicine 
Chief, Division of Endocrinology, Diabetes and Metabolism 
The University of Florida 
1600 SW Archer Rd; Room H -2 
P.O. Box: 100226 
Gainesville, FL 32610-0226 
 
 
 
 
 
 
 
 
 
Confidentiality 
statement 
This information may not be used, published, or otherwise disclosed without the prior written 
authorization from the principal investigator. 

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Signature page 
Study title: Efficacy, Safety and Mechanism of Action of Lanifibranor (IVA337) in Patients with 
Type 2 Diabetes (T2DM) and Nonalcoholic Fatty Liver Disease (NAFLD) 
Study code: lanifibranor/2018 
Principal Investigator and co-Investigators have approved the protocol Version 2.4.3 October 18, 
2021 and confirm hereby to perform this study in compliance with this protocol, the current 
Helsinki Declaration (Appendix A), GCP and applicable regulatory requirements. 
 
INVESTIGATORS 
Kenneth Cusi, M.D., F.A.C.P., F.A.C.E 
Professor of Medicine 
Principal Investigator 
Date: 
Signature : 
Other Investigators: 
Diana Barb, M.D. 
Romina Lomonaco, M.D. 
Eddison Godinez Leiva, MD. 
Date : 
Signature: 
 
 
 

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Revision history 
Version 2.5 February 7th, 2022; Main Revision summary: change related to 
concomitant medications further to new information provided in updated IB 
version 12. Change of pharmacovigilance contractor. Included results of the 
NATIVE study published in the New England Journal of Medicine October 21, 
2021. 
 
 

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Version 2.4.3 October 18, 2021; Main Revision summary: updated information on 
Investigational Product and updated main representative for Inventiva S.A. 
 
 

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Version 2.4.2(b) May 4, 2021; Main Revision summary: updated list of 
investigators and DSMB (Dr. J.M. Muñoz Peña replacing Dr. A. Bianchi); updated 
research coordinator (Chrystal Bailey replacing Danielle Poulton). 
 

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Version 2.4.1. Statistical analysis modified (number of patients reduced based on 
the results from NATIVE on steatosis [primary endpoint in this trial]) 

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2.0. June 12, 2018: Incorporation of FDA and IRB requirements including those 
related to Eligibility Criteria, Stopping Criteria and Safety Monitoring 

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1.0 - February 10, 2018 
Initial  
 

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Synopsis 
Study title: Efficacy, Safety and Mechanism of Action of lanifibranor (IVA337) in Patients with 
Type 2 Diabetes (T2DM) and Nonalcoholic Fatty Liver Disease (NAFLD). 
Study code: Lanifibranor / 2018 
Trial registration: NCT number 
Protocol version and date: Version 2.3, November 27 
Development Phase: II, Investigator Initiated study 
Investigators & study location: 
Principal Investigator: Kenneth Cusi, M.D., F.A.C.P., F.A.C.E 
Chief, Division of Endocrinology, Diabetes and Metabolism 
The University of Florida 
1600 SW Archer Rd; room H -2 
P.O. Box: 100226 
Gainesville, FL 32610-0226 
Studied period: First enrolment: Q3 2018. Expected completion date: Q4 2020. 
Objectives: The primary aim is to establish the safety, efficacy and mechanism of action of 
lanifibranor in patients with Type 2 diabetes (T2DM) and nonalcoholic fatty liver disease 
(NAFLD). Specifically, to determine if lanifibranor decreases intrahepatic triglycerides (IHTG) 
(primary endpoint), improves hepatic insulin sensitivity, endogenous (hepatic) glucose production, 
gluconeogenesis and de novo lipogenesis (DNL). This will be achieved by using a combination of 
intravenously infused stable isotopes and with the infusion of a low- and high-dose insulin infusion 
during a euglycemic hyperinsulinemic clamp with indirect calorimetry. In addition, exploratory 
analysis with surrogate plasma biomarkers and imaging on liver fibrosis changes on with treatment 
will be performed. 
Study design: The study is a two arm (placebo, lanifibranor 800 mg/day), randomized (1:1), 
double-blind, placebo-controlled, 24-week treatment study. There is in addition a non-obese 
subject control group for the metabolic and imaging procedures. 
Study duration: The total time (from first patient enrolled to last patient finished) will be 32±4 
weeks (4-6 weeks for run-in, 24 weeks of treatment and 4 weeks post-study follow-up), with an 
estimated recruitment period of 6-9 months. 
Total number of subjects: 34 randomized to study drug or placebo. Ten healthy non-obese will 
also be studied as “normal controls” for all the metabolic and imaging tests to be performed. 
 
Diagnosis and main criteria for inclusion: 
1. Be able to communicate meaningfully with the investigator and legally competent to 
provide written informed consent 
2. Have an age between 21 to 75 years inclusive 
3. Subjects should be on stable standard of care and background therapy for ongoing chronic 
conditions, including stable doses of anti-diabetic medications, for at least two (2) months 
prior to trial entry 
4. Have uncontrolled diabetes with a fasting plasma glucose (FPG) ≥ 100 mg/dL but ≤ 250 
mg/dL and HbA1c ≥ 6.0% but ≤ 9.5%, on diet alone, or on metformin (≥1,000 mg/day), 
and/or sulfonylurea and/or DPP-IV therapy, SGLT2 inhibitors or GLP1RA. These medicines 
will be continued at stable doses during the entire study. 
a. 
Subjects with an HbA1c > 8.0% but ≤ 9.5% will have their metformin 
(minimum dose required: 1,000 mg/day) maximized to 1,000 mg BID and/or 

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glimepiride 2 mg once daily added during the first 2 weeks of the run-in period. 
The baseline visit to initiate lanifibranor (V4; Time 0 or randomization visit) will be 
not sooner than 8 weeks from diabetes medication titration and the patient should 
have an HbA1c ≤9.0% to proceed to randomization (V4). 
b. In addition, if both metformin and glimepiride (or another sulfonylurea) are already 
maximized at study entry (or the patient is intolerant to either) and the HbA1c ≥ 
9.0% but ≤9.5%, we will add sitagliptin 100 mg daily (or an equivalent dose of 
another DPP-IV inhibitor) to reach an HbA1c ≤9.0% to proceed to randomization 
(V4). 
5. Presence of hepatic steatosis (Intrahepatic Triglycerides IHTG) > 10 % determined by 
Magnetic Resonance and Spectroscopy (1H-MRS). 
6. Have no new symptoms associated with decompensated diabetes in the previous 3 months. 
7. Compensated liver disease with the following hematologic and biochemical criteria on entry 
into protocol: 
o Hemoglobin > 11 g/dL for females and > 12 g/dL for males 
o White blood cell (WBC) > 2.5 K/µL 
o Neutrophil count > 1.5 K/µL 
o Total bilirubin ≤ 1.3 mg/dL (≤ 22.2 µmol/L). Patients with bilirubin ≤ 1.3 
mg/dL can be included if non-conjugated bilirubin in the setting of a Gilbert’s 
syndrome. 
o Albumin > 36 g/L 
8. No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, 
HCV, Wilson’s, α-1-antitrypsin deficiency, hemochromatosis, other). 
9. Negative pregnancy test or at least two-year 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 
progesterone 
containing) 
hormonal/ 
progesterone-only 
hormonal 
contraception associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomized partner). The 
contraceptive method will have to be followed for at least one menstruation cycle after the 
end of the study. 
Exclusion criteria: 
1. Evidence of liver disease other than NAFLD. 
2. History of excessive alcohol intake, defined by ≥ 21 units of alcohol per week in males and 
≥14 units of alcohol per week in females for two years prior to enrollment, where a “unit” of 
alcohol is equivalent to 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor. 
3. Unstable metabolic condition: Weight change > 5 kg in the 3 months prior to enrollment, 
diabetes with poor glycemic control (HgbA1c > 9.5% or FPG > 250 mg/dl), introduction of 
an anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the past 6 
months prior to screening. 
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. 
5. Subjects on sulfonylureas, metformin, GLP-1RA or DPP-IV unless the dose and body weight 
(within 5%) have been stable for at least two (2) months prior to study entry. 
6. Patients on insulin, pioglitazone (or prior use in the past 12 months). 

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7. Patients on any of the following medications unless the patient has been on stable doses of 
such agents for the past two (2) months before entry into the study: thiazide or furosemide 
diuretics, beta- blockers, or other chronic medications with known adverse effects on glucose 
tolerance levels. Patients may be taking stable doses of estrogens or other hormonal 
replacement therapy if the patient has been on these agents for the prior two (2) months. 
Patients taking systemic glucocorticoids will be excluded. 
Treatment with strong inducers or inhibitors of CYP2C8, or treatment with substrates of 
CYP2B6 or CYP2C8. When administered chronically, they should be replaced 2 months 
before trial entry (See Inclusion criterion #3). If not administered chronically, they should be 
stopped at least 7 days before first dosing. 
8. Patients with: 
a. 
History of myopathies or evidence of active muscle diseases 
b. Unstable cardiovascular disease, including: 
i. 
Unstable angina (i.e., new or worsening symptoms of coronary heart 
disease within the past 3 months), acute coronary syndrome within the 
past 6 months, acute myocardial infarction in the past 3 months or heart 
failure of New York Heart Association class (III-IV) or worsening 
congestive heart failure, or coronary artery intervention, within the past 6 
months 
ii. 
History of (within prior 3 months) or current unstable cardiac 
dysrhythmias 
iii. 
Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or 
diastolic blood pressure > 100 mmHg. 
iv. 
Stroke or transient ischemic attack within the prior 6 months 
c. 
History of malignancy in the past 5 years and/or active neoplasm with the exception 
of resolved superficial nonmelanoma skin cancer 
d. History of bladder disease and/or hematuria or has current hematuria unless due to 
a urinary tract infection 
e. 
Any of the following laboratory values: 
ii. 
Serum bilirubin > 1.3 mg/dL (or > 22.2 µmol/L). Patients with bilirubin > 
1.3 mg/dL can be included if non-conjugated bilirubin in the setting of a 
Gilbert’s syndrome. 
iii. 
Serum ALT > 3X ULN 
iv. 
INR > 1.2 
v. 
Platelets < 150,000 per microliter of blood 
vi. 
Renal impairment as demonstrated by estimated glomerular filtration rate 
(eGFR) < 60 mL/min/1.73m2 
vii. 
Total creatinine kinase > 1.5 X ULN 
viii. 
Lipase > 1.3X ULN or >2.0X ULN if on a DPP-IV inhibitor. *(if abnormal 
values are confirmed when repeated within 3 weeks) 
ix. 
Hemoglobin A1c > 9.5% 
9. Significant systemic or major illnesses other than liver disease, including those listed in 
exclusion criteria #8 and pulmonary disease, organ transplantation, serious psychiatric 
disease, that, in the opinion of the investigator, would preclude treatment with lanifibranor 
and/or adequate follow up. 
10. HB antigen > 0, HCV > 0 (patients with a history of HCV infection can be included if HCV 
PCR is negative since more than 3 years), prior history of HIV infection. 
11. Pregnancy/lactation or inability to adhere to adequate contraception in women of child-
bearing potential. 

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12. Any other condition which, in the opinion of the investigator would impede competence or 
compliance or possibly hinder completion of the study. 
13. Body mass index (BMI) > 45 kg/m2. 
14. Type 1 diabetes and type 2 diabetic patient on insulin. 
15. Diabetic ketoacidosis. 
16. Fasting plasma triglycerides > 500 mg/dL. 
17. Hemostasis disorders or current treatment with anticoagulants. 
18. Participation in any other investigational drug study within the previous 3 months. 
19. Have a known hypersensitivity to any of the ingredients or excipients of the IMP including: 
Lactose monohydrate, hypromellose, sodium lauryl sulphate, sodium starch glycolate, 
magnesium stearate, Opadry™ II 85F18422, DSS Granular, cellulose microcrystalline, 
maize starch. 
20. Be possibly dependent on the Investigator (e.g., including, but not limited to, affiliated 
employee). 
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. 
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. 
 
Test product, dose and mode of administration: 
Tablets of lanifibranor 400 mg or placebo, administered on a daily dose of 800 mg lanifibranor or 
placebo, i.e. 2 tablets of 400 mg/placebo orally once daily (QD), during breakfast. 
 
Prohibited concomitant medications: 
• PPAR gamma agonists, PPAR Alpha agonists (fibrates), ezetimibe, 
• Bile salts chelators, phytosterols, fish oils, 
• Insulin, 
• Vitamins E (alpha-tocopherol), 
• Anticoagulants (incl. warfarin, dabigatran, rivaroxaban, apixaban), 
• Systemic steroids (more than physiological replacement of 30 mg of hydrocortisone per 
day). 
• Substrates of CYP2B6 (e.g. artemether, artemisinin, bupropion, coumarins [e.g. warfarin, 
acenocumarol], cyclophosphamide, efavirenz, ifosfamine, mephobarbital, methadone, 
nevirapine, pethidine, propofol, selegiline). However, if medically necessary, these 
treatments can be administered for a single intake, occasionally.  
• Substrates of CYP2C8 (e.g. amodiaquine, clopidogrel, daprodustat, dasabuvir, 
enzalumatide, montelukast, paclitaxel, repaglinide, torasemide). However, if medically 
necessary, these treatments can be administered for a single intake, occasionally. 
• CYP2C8 strong inducers (e.g. pentobarbital, phenytoin, rifampin, rifamycin, secobarbital). 
However, if medically necessary, these treatments can be administered for a single intake, 

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occasionally. 
• CYP2C8 strong inhibitors, when systemically administered, i.e. by oral, intra-venous or 
intra-muscular route of administration (e.g. gemfibrozil, clopidogrel, felodipine, zafirlukast, 
candesartan celixetil, ketoconazole). 
 
Allowable medications for standard care or precautions: 
• Obesity: stable weight defined by no more than a change of 5 kg (see exclusion criteria 
N° 3). 
• 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 2 months before inclusion  
in the study. 
o Type 2 diabetes: 
• Metformin, 
• Sulfonylureas, 
• Dipeptidyl peptidase-4 inhibitors, 
• Sodium-glucose transport protein 2 inhibitors: canagliflozin, dapagliflozin 
and empagliflozin. 
• GLP-1RA 
o Hyperlipidemia: only statins at stable doses will be allowed. 
o Antiplatelets agents: The antiplatelets agents (incl. low-dose aspirin, ticlopidine, 
clopidogrel, prasugrel, ticagrelor) are allowed. 
o Herbal supplements: Herbal preparations or vitamin supplements should not be 
taken as it is difficult to know exactly what they contain and could be liver toxic. 
 
If a symptomatic medication is needed to treat adverse events that may be related to IMP, the 
investigator will inform the Principal Investigator about the concomitant medication given. 
Duration of treatment: lanifibranor or placebo to match 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), hematology, blood 
biochemistry and urinalysis, liver enzymes, oral glucose tolerance test, exploratory biomarkers 
adiponectin, ProC3, CK-18, genotyping. 
Imaging such as fibroscan, liver fibrosis, liver IHTG and T1 MR mapping. 
All patients, insulin sensitivity study: 2-step insulin clamp with glucose turnover measurements. 
 
Primary efficacy criterion. Determine if lanifibranor decreases intrahepatic triglycerides (IHTG) 
(primary endpoint), improves hepatic insulin sensitivity, endogenous (hepatic) glucose production, 
gluconeogenesis and de novo lipogenesis (DNL). 
 
Statistical methods and Safety: 
Sample size: based on the most recent studies, patients with NAFLD are expected to have a mean 
baseline IHTG of approximately 15%. The earlier power calculations were based on results with 
pioglitazone from a 6-month study (1) and a more recent 18-month RCT (2) but they wee revised 
in version 2.4.1 of the protocol based on the results with lanifibranor 800 mg/day (same dose as this 
study) from a 6-month RCT (NATIVE) that used liver biopsy (histology) as the primary endpoint 
(provided in detail by Inventiva to the PI Dr. Cusi). In NATIVE, the proportion of patients with a 
reduction in steatosis to lanifibranor was 73% versus 26% with placebo (steatosis being the primary 
endpoint of this study); being greater than with pioglitazone in the 6-month Belfort et al study 

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[1]). Based on these results, this would translate to liver fat imaging on 1H-MRS of a relative 
reduction of fat liver with lanifibranor to be ≥50% compared to placebo. This represents a 
change of ≥7.0% with lanifibranor versus the control group. The expected standard deviation of 
the change from baseline is expected to be 7%. Considering a type I error of 0.05 (2- sided), a 
power of 0.80, an allocation ratio of 1:1, the same variance in both treatment groups and a 
parametric test of mean comparison, the required sample size per group is 15 patients to complete 
treatment. Assuming that 10 % of randomized patients will not complete the trial, the total number 
of patients to be randomized is 33-34 patients. Considering a type I error of 0.05 (2-sided), a power 
of 0.80, an allocation ratio of 1:1, the same variance in both treatment groups and a parametric test 
of mean comparison the required sample size per group is 15 patients. Assuming that 10 % of 
randomized patients will not complete the trial, the total number of patients to be randomized is 
34. 
Randomization: Patients will be randomized equally 1:1: to either dose of lanifibranor or placebo. 
The randomization list will be setup with blocs of size equal to 4. 
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 Principal 
Investigator will use its most updated list of potentially clinically significant abnormalities (PCSA) 
in clinical laboratory tests, vital signs, and ECG for the final analysis. The effect of the 
demographic differences (gender, age, etc.) and risk factors of clinical relevance will be explored. 
Efficacy variables: 
Primary outcome: Change in IHTG quantified by ¹H-MRS from baseline to 24 weeks 
Secondary endpoints: 
The following changes from baseline to 24 weeks of treatment will be evaluated: 
• Proportion of responders defined as the percentage of patients reaching a decrease from 
baseline in IHTG (quantified by ¹H-MRS) to week 24 of ≥ 30%. The definition of 
“responders” as those with a ≥ 30% reduction in liver fat by ¹H-MRS is empiric as there 
are no studies (except the Belfort et al, NEJM 2006 (1) and Cusi et al (2) with 
pioglitazone) comparing simultaneously ¹H-MRS data with liver histology, but it is 
assumed that such threshold is likely to correlate with positive histological changes in 
NASH, based on the investigator's experience. 
• Proportion of patients with NAFLD  resolution  considered  as  having  ≤  5.5%  IHTG 
(quantified by 1H- MRS) at 24 weeks. 
• Changes in hepatic fibrosis measured by several techniques: 
a) Vibration-controlled transient elastography (Fibroscan) (3); 
b) Two-dimensional magnetic resonance elastography (2D-MRE) (4); and 
c) A novel T1 MRI mapping scanning protocol that allows for the accurate non-invasive 
measurement of liver fibrosis, in collaboration with the Oxford laboratory (5). 
• Change in plasma biomarkers of liver fibrosis (i.e., cytokeratin CK-18, proC3) or clinical 
laboratories. 
• Change in metabolic outcomes standard for such pilot trials (see ref. 1, 2, and 6) at week 
24 of treatment, and will include: 
o Determination of hepatic insulin sensitivity 
o De novo lipogenesis 
o Glycemic control: HbA1c, 
o Advanced lipid testing. 
Study procedures: 
All patients will undergo ten visits, screening V1 to V3 (-6 weeks to -1 week), randomization V4 

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(time 0), follow-up V5 (week 4), follow-up V6 (week 8), follow-up V7 (week 12), follow-up V8 
(week 16), follow-up V9 (week 20), repeated baseline studies at V10 (week 23), V11 (week 
24), and off-drug follow-up V12 (week 28). For all visits time windows are defined up to +/- 5 
days compared to V1 and are indicated in the Table 1. 
Patients will be randomized to either dose of lanifibranor or placebo at V4 and treated for 24 weeks 
until V11. Please note that due to COVID-19 pandemic, in order to be able to accommodate important 
follow-up study procedures, for some of the already enrolled subjects, treatment with lanifibranor 
may have to be extended by 1-8 weeks. This time frame will allow completion of the follow-up liver 
MRI (V10) and perform the insulin clamp (V11). These are essential procedures in order to obtain 
the primary and secondary outcomes of the study. 
A vital signs, weight, height and waist measurements will be performed at each visit. An ECG 
will be done at screening (V1) and at end of treatment (V11). A physical exam including weight 
measurement every 4 weeks once patients randomized to study medication. Adverse events and 
concomitant medications will be recorded throughout the study. Patients and caregivers will be 
educated for potential symptoms of adverse effects that should be reported to the investigators, 
such as skeletal muscle pain, weight gain, peripheral edema, shortness of breath, etc. If a patient 
has symptoms of dyspnea, edema, or a presumptive diagnosis of heart failure, NT-proBNP should 
be measured as close to the event as possible. The potential for hypoglycemia will be monitored 
carefully, particularly in patients on anti-diabetic medications, as detailed in the protocol. 
The routine laboratory assessments performed at V1, V4, V5, V6, V7, V8, V9 V11 and V12 will 
include: complete blood count, comprehensive metabolic profile and lipids. CK and CK-MB will 
be measured every 4 weeks once the patient is randomized to study medication. 
Urine Samples will be collected at V1, V11 and at V12. 
Urine pregnancy test will be performed at V1, V4, V7, V9, V11 and V12. 
 
Figure 1.        Study Design 
 

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Table 1. 
Study Schedule of procedures 
 
 
 
Inventiva Study 
n = 34 patients with T2DM and 10 healthy non-obese controls (controls only to undergo OGTT and euglycemic insulin clamp) 
Principal Investigator: Kenneth Cusi, MD 
Institution: University of Florida 
Run-in period 
Study Period 
Screen 
DM med titration 
Repeat baseline studies 
Follow-up 
VISIT 
V1 
V2 
V3 
V4 
V5 
 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
Study Day (+/- 5 days) 
-42 
-28 
-7 
-7 and 0 
28 
56 
84 
112 
140 
161 
167 and 168 
196 
Weeks 
-6 
-4 
-1 
Time 0 Randomization 
4 
8 
12 
16 
20 
23 
23 to 24 
28 
Key procedure per visit 
Screen + fibroscan 
Medication titration 
Liver imaging Ins. sensitivity, DNL, GNG 
follow-up 
follow-up 
follow-up 
follow-up 
follow-up 
Liver imaging 
Ins. sensitivity, DNL, GNG 
off-drug f/u 
Procedure 
Sign informed consent form 
X 
Review Eligibility (inclusion/exclusion criteria) 
X 
Medical History 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol screen (AUDIT questionnaire) 
X 
X 
Drug screen 
X 
Serology: HIV,  HB antigen, HCV PCR, ferritin* 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs, Weight/Ht, waist measurement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
† Routine Chems (CBC, CMP, lipids, CPK, CPK-MB, 
serum creatinine, eGFR, lipase) 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1c 
X 
X # 
X 
X 
X 
X 
X 
TSH, free T4* 
X 
Urinalysis 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
FSH (postmenopausal patients only) 
X 
STAFF  ASSESSMENTS 
Outpatient nursing staff assessment 
X 
X 
X 
X 
X 
X 
X 
Study Coordinator assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician assessment 
X 
X 
X 
X 
X 
X 
X 
Review subject glucose records 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess study drug compliance 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary counseling 
X 
X 
X 
Hypoglycemia counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
Research Pharmacy Drug Dispensation 
X 
X 
X 
AE Reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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OUTCOME LABORATORIES 
Fasting Plasma Glucose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Fingerstick Glucose 
X 
X 
Advanced lipid panel (lipoproteins, particle #/size) 
X 
X 
X 
Adiponectin 
X 
X 
X 
Exploratory biomarkers (cytokines) 
X 
X 
X 
X 
Fibrosis panel (Fibrotest) 
X 
X 
ProC3 (Nordic) 
X 
X 
X 
CK-18 
X 
X 
Genotyping (SNPs of interest) 
X 
IMAGING 
CAP and VCTE (Fibroscan) 
X 
X 
Liver IHTG content (1H-MRS) 
X 
X 
Liver fibrosis (MRE) 
X 
X 
T1 MR mapping 
X 
X 
INPATIENT METABOLIC TESTING 
Admit to CRC (research unit) 
X 
X 
Discharge from CRC 
X 
X 
Inpatient nursing staff assessment 
X 
X 
Study coordinator inpatient care 
X 
X 
Physician inpatient care 
X 
X 
Meal at CRC 
X 
X 
Overnight stay 
X 
X 
Insulin sensitivity study (clamp) with 6-6-2H glu infusion 
X 
X 
De novo lipogenesis (DNL) and gluconeogenesis 
X 
X 
Indirect calorimetry 
X 
X 
Urine collection for metabolic measurements 
X 
X 
* Not necessary if vailable within the past 12 months 
† CBC (complete blood count) 
Red blood cell count, hemoglobin, hematocrit, WBC w/diff, platelet count. 
† CMP (comprehensive metabolic profile) 
Glucose, electrolytes, albumin, total protein, calcium, bilirubin (BR), AST, ALT, alk phos (ALP), INR. 
† Lipids 
Total cholesterol, HDL-C, LDL-C, non-HDL-C, triglycerides. 
# only if diabetes treatment modified since 
screening 

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Table of contents 
SIGNATURE PAGE ......................................................................................................................... 2 
REVISION HISTORY ..................................................................................................................... 3 
SYNOPSIS ......................................................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 23 
1 
INTRODUCTION ........................................................................................................ 26 
1.1 
Study Rationale ............................................................................................................. 26 
1.2 
Previous Studies in Patients NAFLD/NASH and T2DM and Interest of Assessing 
the Metabolic Effects of the Pan-PPAR IVA337 ........................................................ 27 
1.3 
Investigational Product ................................................................................................ 28 
1.4 
Summary of Lanifibranor Preclinical and Clinical Data........................................... 29 
1.4.1 
Pharmacology ............................................................................................................................. 29 
1.4.2 
Pharmacokinetics ........................................................................................................................ 30 
1.4.3 
Toxicology .................................................................................................................................. 31 
1.4.4 
Previous IVA337 Clinical Data .................................................................................................. 34 
1.5 
Rationale of the Study Design ...................................................................................... 35 
1.5.1 
General Considerations ............................................................................................................... 35 
1.5.2 
Rationale for the Choice of Dose and Duration of Repeated Administration .............................. 35 
2 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ................. 36 
2.1 
Investigators and Other Participants .......................................................................... 36 
2.2 
Role of Inventiva SA and Representatives .................................................................. 36 
2.3 
Pharmacovigilance and Safety ..................................................................................... 37 
2.4 
Other Relevant Institutions .......................................................................................... 37 
3 
ETHICAL AND LEGAL CONSIDERATIONS ........................................................ 37 
3.1 
Institutional  Review  Board  (IRB)/Independent  Ethics  Committee (IEC) ........ 37 
3.2 
Protocol Amendments .................................................................................................. 38 
3.3 
Ethical Conduct of the Study ....................................................................................... 38 
3.4 
Good Clinical Practice Responsibilities ....................................................................... 38 
3.5 
Reporting of Safety Issues Breaches of the Protocol or ICH GCP ............................ 38 
3.6 
Insurance ....................................................................................................................... 38 
3.7 
Patient Information and Consent ................................................................................ 39 
3.8 
Premature Termination ............................................................................................... 39 
3.9 
Definition of End of the Trial ....................................................................................... 39 
4 
STUDY OBJECTIVES AND INVESTIGATIONAL PLAN .................................... 39 
4.1 
Aim ................................................................................................................................ 39 
4.2 
Study Design ................................................................................................................. 39 
4.2.1 
Screening Phase .......................................................................................................................... 40 
4.2.2 
Intervention Period (24 weeks) ................................................................................................... 41 
4.2.3 
Off-study Drug Follow-up Period (4 weeks) ............................................................................... 42 
4.2.4 
Patient Management at the End of Treatment ............................................................................. 42 
4.2.5 
Total Study Duration .................................................................................................................. 42 
4.3 
Study Population and Inclusion/Non-inclusion Criteria ............................................ 43 
4.3.1 
Inclusion Criteria ........................................................................................................................ 43 
4.3.2 
Non-Inclusion Criteria ................................................................................................................ 44 

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4.3.3 
Prohibited Concomitant Medications .......................................................................................... 46 
4.3.4 
Enrollment .................................................................................................................................. 47 
4.4 
Study Medication .......................................................................................................... 47 
4.4.1 
Identity of Investigational Medicinal Product(s) (IMP) .............................................................. 47 
4.4.2 
Treatments Administered ............................................................................................................ 47 
4.4.3 
Medication Dispensing ............................................................................................................... 48 
4.4.4 
Selection and Timing of Dose for Each Patient .......................................................................... 48 
4.4.5 
Labeling ...................................................................................................................................... 48 
4.4.6 
Accountability ............................................................................................................................ 50 
4.4.7 
Treatment Compliance ................................................................................................................ 50 
4.4.8 
Return or Destruction of Investigational Products ...................................................................... 50 
5 
MEASUREMENTS ASSESSED AND STUDY FLOW CHART ............................ 50 
5.1 
Table of Study Procedures and Assessments .............................................................. 50 
5.2 
Specific Procedures for Assessment of Outcomes ...................................................... 50 
5.2.1 
Urine Samples ............................................................................................................................. 50 
5.2.2 
Blood Samples Taken ................................................................................................................. 51 
5.2.3 
Waist Measurement .................................................................................................................... 51 
5.2.4 
Electrocardiogram ....................................................................................................................... 52 
5.2.5 
Vital Signs .................................................................................................................................. 52 
5.3 
Procedures at Each Visit .............................................................................................. 52 
5.3.1 
Screening (V1) ............................................................................................................................ 52 
5.3.2 
Medication Titration (V2) at Week -4 ......................................................................................... 53 
5.3.3 
Baseline Visit (V3) at Week -1 ................................................................................................... 53 
5.3.4 
Randomization Time 0 (V4) ....................................................................................................... 53 
5.3.5 
Follow-up Visits (V5) at Week 4, (V6) at Week 8, (V7) at Week 12, (V8) at Week 16 and (V9) 
at week 20 .................................................................................................................................. 53 
5.3.6 
Repeat Baseline Studies (V10) at Week 23 and at (V11) at Week 24 ........................................ 54 
5.3.7 
Off-Drug Follow-up (V12) at Week 28 ...................................................................................... 54 
5.3.8 
Unscheduled/Safety Visits .......................................................................................................... 55 
6 
SAFETY ASSESSMENT ............................................................................................. 55 
6.1 
Adverse Events .............................................................................................................. 55 
6.1.1 
Definitions .................................................................................................................................. 55 
6.1.2 
Collection ................................................................................................................................... 56 
6.1.3 
Intensity Rating ........................................................................................................................... 56 
6.1.4 
Causality Rating.......................................................................................................................... 57 
6.1.5 
Action Taken .............................................................................................................................. 57 
6.1.6 
Outcome ..................................................................................................................................... 57 
6.1.7 
Multiple Signs or Symptoms ...................................................................................................... 57 
6.1.8 
Worsening Signs ......................................................................................................................... 57 
6.2 
Serious Adverse Events ................................................................................................ 58 
6.2.1 
Definitions .................................................................................................................................. 58 
6.3 
Reporting requirements ............................................................................................... 58 
6.3.1 
Immediate reporting .................................................................................................................... 58 
6.3.2 
IND safety reporting requirements .............................................................................................. 59 
6.3.3 
Reporting to Inventiva SA .......................................................................................................... 59 
6.3.4 
Cross-reporting ........................................................................................................................... 59 

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6.4 
Safety Variables ............................................................................................................ 59 
6.4.1 
Physical Examination .................................................................................................................. 60 
6.4.2 
Laboratory Tests ......................................................................................................................... 60 
6.4.3 
Vital Signs .................................................................................................................................. 62 
6.4.4 
Electrocardiogram ....................................................................................................................... 62 
6.5 
Data Safety Monitoring Committee ............................................................................ 62 
7 
DATA QUALITY ASSURANCE ................................................................................ 63 
7.1 
Monitoring .................................................................................................................... 63 
7.2 
Data Recording ............................................................................................................. 64 
7.3 
Data Management ......................................................................................................... 66 
7.3.1 
Responsibilities ........................................................................................................................... 66 
7.3.2 
Data Collection and Validation ................................................................................................... 66 
7.3.3 
Data Coding ................................................................................................................................ 66 
7.3.4 
Database Lock ............................................................................................................................ 67 
7.3.5 
Database Transfer ....................................................................................................................... 67 
7.4 
Independent Audit ........................................................................................................ 67 
7.5 
Regulatory Inspection................................................................................................... 67 
8 
STATISTICAL METHODS ........................................................................................ 67 
8.2 
Sample Size.................................................................................................................... 68 
8.3 
Randomization .............................................................................................................. 69 
8.4 
Protocol Deviations ....................................................................................................... 69 
8.5 
Data sets Analyzed ........................................................................................................ 69 
8.6 
Demographic and Other Baseline Characteristics ..................................................... 70 
8.6.1 
Patient Demographic Characteristics, Medical History and Diagnoses ....................................... 70 
8.6.2 
Previous Medications .................................................................................................................. 70 
8.6.3 
Patient history ............................................................................................................................. 70 
8.7 
Safety Analysis .............................................................................................................. 70 
8.7.1 
Extent of Exposure...................................................................................................................... 70 
8.7.2 
Adverse Events ........................................................................................................................... 70 
8.7.3 
Other Observations Related to Safety ......................................................................................... 71 
8.7.4 
Efficacy Analyses ....................................................................................................................... 72 
9 
PATIENT WITHDRAWAL & REPLACEMENT & CLINICAL TRIAL 
STOPPING RULES ..................................................................................................... 74 
9.1 
Patient Withdrawal ...................................................................................................... 74 
9.2 
Study Stopping Rules ................................................................................................... 75 
9.3 
Unblinding Process ....................................................................................................... 76 
9.3.1 
Unblinding for emergency .......................................................................................................... 76 
9.3.2 
Unblinding for DSMB ................................................................................................................ 76 
9.3.3 
Unblinding at End of Trial .......................................................................................................... 76 
10 
TRAINING & INFORMATION ................................................................................. 76 
10.1 
Training ......................................................................................................................... 76 
10.2 
Information of the Investigator ................................................................................... 77 
11 
RECORDS & DATA .................................................................................................... 77 
11.1 
Source Records & Data ................................................................................................ 77 
11.2 
Case Report Forms ....................................................................................................... 77 

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12 
CONFIDENTIALITY .................................................................................................. 77 
12.1 
Confidentiality of Patient Data .................................................................................... 77 
12.2 
Confidentiality of Data ................................................................................................. 78 
13 
REPORTING & PUBLICATION .............................................................................. 78 
13.1 
Study Report ................................................................................................................. 78 
13.2 
Disclosure of Data and Publications ............................................................................ 78 
14 
RECORD KEEPING ................................................................................................... 79 
14.1 
Study Site Records ........................................................................................................ 79 
14.2 
Study Master File ......................................................................................................... 79 
15 
BIBLIOGRAPHY ........................................................................................................ 79 
16 
APPENDICES .............................................................................................................. 82 
16.1 
Appendix A: World Medical Association Declaration of Helsinki ............................ 82 
16.2 
Appendix B: Methods and Normal Values for Vital Signs, Waist and ECG .......... 90 
16.3 
Appendix C: Procedure for Preparation of (6,6-D2)-Glucose Infusates ..................... 91 
 
 

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List of Tables 
 
Table 1. 
Study Schedule of procedures ......................................................................................... 16 
Table 2. 
Interspecies Comparison of Human and Animal Plasma Exposure to IVA337 in General 
Toxicity Studies ............................................................................................................... 32 
Table 3. 
Interspecies Comparison of Human and Animal Plasma Exposure to IVA337 in 
Segment II Reproductive Toxicity Studies ...................................................................... 32 
Table 4. 
Summary of Labeling Details .......................................................................................... 48 
Table 5. 
Blood Volume Taken at Each Visit per Type .................................................................. 51 
Table 6. 
Laboratory Tests .............................................................................................................. 60 
 
 
List of Figures 
Figure 1.        Study Design .............................................................................................................. 15 
Figure 2.        IVA337 Reduces Inflammation and Steatosis in a 3 Weeks MCD Model ................. 30 
Figure 3.        Phase IIa Biomarkers of IVA337 PPAR Activation in Diabetic Patients ................... 35 
 
 
 

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List of Abbreviations and Definitions of terms 
¹H-MRS 
Proton magnetic resonance spectroscopy 
2D-MRE 
Two-dimensional magnetic resonance elastography 
AE 
Adverse event 
AHA 
American Heart Association 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AST 
Aspartate amino transferase 
AUC 
Area under the curve 
BCS 
Biopharmaceutics classification system 
BDFDCS 
Biopharmaceutics drug disposition classification system 
BLM 
Baseline measure 
BMD 
Bone mineral density 
BMI 
Body mass index 
CA 
Competent authority 
CAP 
Controlled attenuation parameter 
CBC 
Complete blood count 
Cmax 
Maximal plasma concentration 
CPK 
Creatine phosphokinase 
CRC 
Clinical research unit 
CRF 
Case report forms 
CRO 
Contract research organization 
CTSI 
Clinical Translational Science Institute 
CVD 
Cardiovascular disease 
CYP 
Cytochromes P450 
D 
Day 
D2O 
Deuterium labeled water 
DBP 
Diastolic blood pressure 
DM 
Diabetes mellitus 
DNA 
Deoxyribonucleic acid 
DNL 
De novo lipogenesis 
DPP-IV 
Dipeptidyl peptidase IV 
DcSSc 
Diffuse cutaneous systemic sclerosis 
DSMB 
Data safety and monitoring board 
ECG 
Electrocardiogram 
ECM 
Extra-cellular matrix 
eCRF 
Electronic case report forms 
EDC 
Electronic data capture 
EGP 
Endogenous glucose production 
EMA 
European Medicines Agency 
ET 
Early termination 
FAS 
Full analysis set 

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FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
γGT 
Gamma glutamyl transpeptidase 
GCP 
Good Clinical Practice 
GLP-1RA 
Glucagon-like peptide-1 receptor agonists 
1H-MRS 
Magnetic Resonance and Spectroscopy 
h 
Hour(s) 
HbA1c 
Glycosylated hemoglobin A1c 
HBV 
B virus hepatitis 
HCV 
C virus hepatitis 
HIV 
Human immunodeficiency virus 
HDL-C 
High-density lipoprotein cholesterol 
HDPE 
High-density polyethylene 
HOMA 
Homeostasis model assessment of insulin resistance 
HSC 
Hepatic stellate cells 
hs-CRP 
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonization of Technical 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IHTG 
Intrahepatic triglycerides 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
K/µL 
103 cells/microliter 
LDL-C 
Low density lipoprotein cholesterol 
L/kg 
liter/kilogram 
LXR 
Liver X receptor 
ml 
Milliliters 
ml/dL 
Milliliters/deciliter 
min 
Minutes 
µM 
Micromolar 
MCD 
Methionine choline deficient 
MCP 
Monocyte chemoattractant protein 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram 
MH 
Medical history 
MRI 
Magnetic resonance imaging 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic steatohepatitis 
PCP 
Primary care practitioner 
PCR 
Polymerase chain reaction 
PCSA 
Potentially clinically significant abnormalities 

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PDGF 
Platelet-derived growth factor 
PHI 
Personal Health Information 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
PPAR 
Peroxisome proliferator-activated receptor 
PTM 
Placebo to match 
QD 
Once a day (Quaque Die) 
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 
RH 
Relative humidity 
SAE 
Serious adverse event 
SAF 
Steatosis activity fibrosis 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SGLT2 
Sodium-glucose co-transporter-2 
SMA 
α-Smooth muscle actin 
SNP 
Single nucleotide 
SO 
Safety officer 
SUSAR 
Suspected unexpected serious adverse reaction 
TCA cycle 
Tricarboxylic acid cycle enzyme activities 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TMF 
Trial master file 
TP 
Prothrombin Time 
T1 MRI 
Magnetic resonance imaging 
T2DM 
Type 2 diabetes mellitus 
UF 
University of Florida 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper limit of the normal range 
UUO 
Unilateral ureteral obstruction 
V 
Visit 
VLDL 
Very-low-density lipoprotein 
VCTE-CAP 
Vibration-controlled ttransient elastography and continuous attenuation parameter 
Vz/F 
Mean apparent volume of distribution 
WBC 
White blood cell 
 

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1 
INTRODUCTION 
This is a Phase II, randomized, double-blind, placebo-controlled, single-center,  investigator 
initiated, 24-week treatment study of lanifibranor (IVA337) in adult subjects with Type 2 diabetes 
(T2DM) and nonalcoholic fatty liver disease (NAFLD). 
This introductory section provides a rationale for the study, describes the underlying conditions of 
the patients to be included in the study, the scientific rationale for exploring lanifibranor in 
NAFLD, summarizes the lanifibranor preclinical and clinical data. 
 
1.1 
Study Rationale 
Nonalcoholic fatty liver disease (NAFLD) develops in ~70% of patients with type 2 diabetes 
mellitus (T2DM) (7,8) and about 40% develop the more severe form of the disease with hepatocyte 
necrosis (ballooning) and liver inflammation (steatohepatitis or NASH). This is often in diabetes 
associated with fibrosis progression and a higher risk of developing cirrhosis. Of note, diabetes is 
the single most important clinical risk factor for NASH progression. This is particularly true in the 
setting of obesity, where insulin-resistant (dysfunctional) adipose tissue promotes hepatic steatosis 
and hepatocyte injury from “lipotoxicity” (12). Patients with T2DM and NASH are also at 
increased risk of micro- and macrovascular complications (7-13). Taken together, it is likely that 
clinicians managing patients with T2DM will give preeminence to treatments that not only control 
hyperglycemia, but also treat liver disease (NASH). Unfortunately, treatment options for 
NAFLD/NASH remain limited although many drugs are in development, as reviewed recently 
elsewhere (13,14). Successful treatments for NASH will likely need to reverse liver insulin 
resistance (7,8 - see below). Lanifibranor (IVA337), a pan-PPAR α, δ and γ, may improve or 
normalize hepatic insulin sensitivity, intrahepatic triglyceride (IHTG) accumulation, excessive de 
novo lipogenesis (DNL) and VLDL oversecretion (i.e., atherogenic dyslipidemia) in humans but 
this remains to be tested. This may be due to either a direct effect on intracellular glucose or lipid 
metabolism effects in hepatocytes, kupfer and stellate cells. As obesity reaches epidemic 
proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient 
referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in 
NAFLD and common conditions such as metabolic syndrome, T2DM, and cardiovascular disease. 
The following focuses on the pathophysiology of interactions between adipose tissue and target 
organs in obesity and the resulting clinical implications for the management of nonalcoholic 
steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes 
results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in 
ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory 
pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional 
adipocytes and the liver involves multiple cell populations, including macrophages and other 
immune cells that in concert promote the development of lipotoxic liver disease, a term that more 
accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, 
adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. 
Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity 
(e.g., significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory 
pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of 
NAFLD, although their long-term safety and efficacy remain to be established. Better understanding 
of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will 
result in improvements in the clinical management of these challenging patients (7), or indirectly, 
through PPAR δ and/or γ effects on peripheral adipose tissue or muscle insulin signaling pathways. 
This study will test the hypothesis that treatment with lanifibranor will significantly decrease liver 
steatosis (primary endpoint) in patients with T2DM and NAFLD. It will also aim to understand the 
mechanism(s) of action of IVA337 associated with a reduction in liver fat. Specifically, we will 
examine the effect of IVA337 on hepatic pathways linked to the development of hepatic steatosis, 

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insulin resistance and atherogenic dyslipidemia (hepatic insulin sensitivity, endogenous [largely 
hepatic] glucose production and gluconeogenesis, DNL and VLDL secretion) with the use of gold- 
standard stable isotope metabolic techniques. This will establish a robust rationale for the use of 
IVA337 in NAFLD and will complement the results of the Phase IIb RCT (NATIVE trial) on its 
effect on liver histology in NASH, where there was a significant improvement in the primary 
endpoint (SAF-A score and no worsening of fibrosis in 48% with 800 mg/day (p=0.07) and in 55% 
with 1,200 mg/day of lanifbranor (p=0.007) vs. 33% with placebo.  Secondary endpoints significant 
with both doses included resolution of NASH without worsening of fibrosis were and in the 
composite endpoint of resolution of NASH and improvement of fibrosis. 
 
1.2 
Previous Studies in Patients NAFLD/NASH and T2DM and Interest 
of Assessing the Metabolic Effects of the Pan-PPAR IVA337 
There is limited data on pharmacological treatments for this population (13,14). Treatment of 
NASH with DPP-IV inhibitors have met mixed results in NAFLD (8,13), while the potential of 
GLP-1RAs is more promising. For instance, during clinical development it was observed that 
liraglutide lowered elevated plasma aminotransferases in patients with T2DM (15). However, it 
was not until recently that GLP-1RAs were reported to reverse metabolic (16) and histological 
(17) defects in NASH. In the study by Armstrong et al (17), resolution of NASH occurred in 39% 
of patients treated with liraglutide versus 9% treated with placebo (p=0.019; treatment difference 
~30%). Of note, liraglutide improved some but not all histological features. There was a decrease 
in steatosis (83% vs. 45%; p=0.009; ~35% reduction in mean steatosis cores from baseline) and 
hepatocyte ballooning (61% vs. 32%; p=0.05). Insulin sensitivity at the level of the liver and 
adipose tissue improved in a subset of patients undergoing in-depth metabolic studies at 3 months 
(16). However, the study was small and only one-third of patients had T2DM. Moreover, recently 
Tang et al (18) recently reported no effect of liraglutide on liver fat in patients with T2DM and 
NAFLD. Therefore, the role of GLP-1RAs in patients with T2DM and NAFLD remains to be fully 
established. 
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins that function as 
transcription factors regulating the expression of genes essential for cellular differentiation, and 
development, as well as in key pathways of carbohydrate, lipid and protein (1). PPARα is highly 
expressed in the liver and its activation by fibrates modulates fatty acid transport and β-oxidation, 
inflammatory pathways, and improves the plasma lipoprotein profile observed in insulin-resistant 
states, but not glucose metabolism (19). Moreover, fibrates do not reduce hepatic triglyceride 
concentration in NAFLD (20). PPARδ agonists also promote fatty acid transport and β-oxidation, 
increase plasma HDL-C concentration, and exert anti-inflammatory actions in macrophages and 
Kupffer cells (19), but in addition may improve glucose metabolism by enhancing insulin hepatic 
insulin sensitivity (21,22). These features are attractive for the treatment of NASH. However, 
recently elafibranor, a PPARα/δ agonist, failed to meet the primary endpoint of resolution of 
NASH in the GOLDEN trial but reported histological benefit in patients with a higher NAS score 
(≥ 4) (23). Thiazolinediones (TZDs) are ligands for the transcription factor PPAR-γ that plays a 
key role in the regulation of glucose and lipid metabolism, as well as in inflammation. Belfort et al 
were the first to report in a RCT that a PPAR-γ ligand (pioglitazone) could improve liver 
histology in patients with NASH and also having prediabetes or T2DM (1). There was also a 
suggestion that fibrosis could be reversed in NASH, as pioglitazone-treated patients had a 
significant reduction in liver fibrosis compared to baseline, although this fell short of reaching 
statistical significance when compared to placebo (p=0.08). This was later also demonstrated in 
non-diabetic patients (7,14). Recently, Cusi et al. reported in a 36-month study in 101 patients with 
prediabetes or T2DM and NASH that pioglitazone led to sustained histological and metabolic 
benefit (2). Of note, there was also a modest but statistically significant difference in the mean 
scores for fibrosis when compared to placebo. The effect of pioglitazone in patients with advanced 
fibrosis (F2-3) has been suggested from a recent meta-analysis combining all recent RCTs (24). 

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Animal models of NASH offer powerful evidence that the pan-PPAR IVA337 can improve insulin 
action, increase adiponectin, improve liver histology and have anti-inflammatory and anti- fibrotic 
properties (data on file Inventiva and 25). It is also likely that IVA337 may improve mitochondrial 
defects that are at the core of the paradigm linking excess substrate supply (fatty acids), insulin 
resistance, hepatocyte “lipotoxicity” and steatohepatitis, as recently reviewed (26,27). Recent 
studies from our laboratory (28,29), and others (30,31), support the role of mitochondrial 
dysfunction in NASH. Recent human studies indicate inadequate mitochondrial adaptation despite 
increased TCA cycle activity in obese patients with NASH (32) and we have developed the 
methodology to study mitochondrial function in clinical trials (33). 
In humans, the mechanism of action of IVA337 remains to be further assessed. In the 4-week 
PK/PD Phase IIa study in patients with T2DM, IVA337 had a mild glucose-lowering effect. It is 
unclear if the limited glucose-lowering effect was due to a lack of efficacy per se or was related to 
the short-term 4- week exposure. However, treatment improved lipids and markedly increased 
plasma adiponectin concentration. As mentioned above, liver histology improved in the Phase IIb 
NATIVE RCT, being important at the same time to establish the mechanism of action and metabolic 
effects of IVA337 on hepatic, muscle and/or adipose tissue insulin sensitivity in patients in NASH, 
as reported for liraglutide (16,17) or pioglitazone (1,2) in insulin-resistant and/or T2DM patients. 
An attractive feature of IVA337 is its ability to impact through its PPAR α/δ profile lipid pathways 
and likely reduce increased rates of DNL and hepatic VLDL secretion that drive the atherogenic 
dyslipidemia and CVD in NAFLD. Pioglitazone, possibly by its PPAR α properties, has been 
reported to reduce DNL in humans (34) and lower plasma triglyceride concentration in association 
with an improvement in mitochondrial defects that drive hepatic steatohepatitis (7,31). Treatment 
with IVA337 would be well suited to address these defects but requires additional investigations in 
T2DM. 
In summary, given IVA337’s apparent clinical efficacy and overall safety (i.e., a PPAR that is 
apparently weight neutral and does not cause fluid retention), it may hold a significant advantage 
over traditional PPARγ agonists and other drugs in development for NASH. We hypothesize that 
IVA337 will have a profound impact on liver metabolism, reducing hepatic triglyceride content 
and improving hepatic insulin sensitivity in patients with T2DM and NAFLD/NASH. Therapies 
that can reduce hepatic steatosis/TG synthesis/DNL and VLDL oversecretion will likely become 
first-line therapy for patients with T2DM and NASH. This work will open a new horizon for 
IVA337 as an insulin-sensitizer and position it as a key player in the management of these patients. 
 
1.3 
Investigational Product 
Lanifibranor (IVA337), 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-gelatinized starch and magnesium stearate serve as placebo. 
The Investigational Medicinal Products used in this clinical Phase II trial will be packaged in 

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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. 
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. 
A new formulation has been developed to reduce the size of the lanifibranor tablet and improve 
compliance to the treatment. The two formulations are be considered as similar as demonstrated by 
a bio-equivalence clinical study (337HVPK18006 trial). All characteristics of the investigational 
product remain the same except that the new formulated lanifibranor tablet has a weigh of 
approximately 721 mg and a shelf life is of 3 years based on the results of the ongoing stability 
studies. 
Matching film-coated tablets with a core containing 700 mg of a physical mixture of lactose 
monohydrate, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate have also 
been developed to serve as placebo. 
Upon protocol approval, any new subject enrolled will be administered with the new formulation. 
For subjects under treatment, the switch to the new formulation will be made at the next study visit 
post protocol approval with respect to the initial assignment to treatment arm. 
 
1.4 
Summary of Lanifibranor Preclinical and Clinical Data 
1.4.1 
Pharmacology 
NAFLD/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 IVA337 in several components of the metabolic syndrome as well as in fibrosis. 
IVA337, 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, IVA337 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 IVA337 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, IVA337 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 IVA337 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). IVA337 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 

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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. IVA337 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 IVA337 in the target cells. 
Activity of IVA337 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 IVA337 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). IVA337 also prevented 
inflammation at the doses of 10 and 30 mg/kg (-44.03% and -74.49% respectively compared to 
vehicle). IVA337 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.        IVA337 Reduces Inflammation and Steatosis in a 3 Weeks MCD Model 
 
 
 
1.4.2 
Pharmacokinetics 
IVA337 can be considered as a class II compound as regard to the Biopharmaceutics Classification 
System (BCS) Guidance and Biopharmaceutics Drug Disposition Classification System 
(BDDCS): high permeability and metabolism, and low solubility. It was evidenced in all tested 
pecies that IVA337 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 humans, maximum plasma levels (Cmax) of IVA337 were reached at 
about 1.0-3.5 hours, and terminal plasma elimination half-life was around 10-15 h. Both AUC and 
Cmax increased in a linear but slightly less than dose-proportional manner. Steady-state IVA337 
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. 
IVA337 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, IVA337 was shown to be mainly distributed in the excretory organs (liver, 

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kidneys, lungs, gastrointestinal tract) and in placenta in pregnant rats with no affinity for the 
melanin tissues and with very limited central nervous system distribution. 
IVA337-related radioactivity elimination in human was mainly fecal (> 85%) and the urinary 
excretion was minor (< 7%) with a very low renal clearance. The excretion was essentially 
complete after 3 days. 
AUC indicated that approximately 23% of the radioactivity in human plasma were related to 
IVA337, while 77% were related to its metabolites. 
Among metabolites identified in plasma, feces and urine, the main IVA337 metabolites observed 
in human were the acylglucuronide (IV1197736, with similar exposure to that of the parent 
compound), a monohydroxylated (IV1537661) and the benzothiazole ring opened IVA337 
derivative (IV1197347). All other metabolites were reported to represent less than 5% 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. 
In vitro data on drug-drug interaction of IVA337 and its three main human metabolites were 
completed. The data interpretation was done following EMA and FDA guidelines on the 
investigation of drug interactions, considering the therapeutic dose of 1200 mg (Cmax ~20 µM) and 
estimated parameters (Ka, Fa) from population PK modelling. 
As victim, the pharmacokinetic of IVA337 or its main human metabolites was observed in vitro to 
be possibly sensitive to the pathways CYP2C8, CYP2C19, CYP3A4, UGT1A1, UGT1A3, 
UGT2B7, MRP2, MRP3, OATP1B1 and OATP1B3. As several isoforms of each enzyme are 
involved (CYP and UGT), a risk of clinical interaction via these pathways is reduced. Nevertheless, 
the contribution of CYP isoforms to the formation of the main Phase I metabolites is still to be 
exemplified. As regards to transporters, clinical data would be required to assess the possible 
interaction of comedications on the IVA337 via these pathways. 
As perpetrator, in vitro studies evidenced that IVA337 or its main human metabolites may have an 
impact on the pharmacokinetics of drugs which are sensitive to the pathways CYP2B6, CYP2C8, 
UGT1A1, UGT1A4, UGT2B7, BCRP, MRP2, MRP3, OATP1B1, OATP1B3, and at the intestine 
level MDR1, and at the kidney level OAT1 and OAT3. In silico modelling will be conducted for a 
deeper analysis on the CYP and OAT interactions. As regards to MDR1, BCRP, OATP and MRP 
transporters, clinical studies would be conducted to assess the possible interaction of IVA337 on 
comedications via these pathways. A first study was performed with simvastatin, substrate of 
several pathways (MDR1, BCRP, OATP1B1 but also CYP3A4 and CYP2C8), which seemed not 
to evidence a significant drug-drug interaction (< 2-fold) although the increase of simvastatin Cmax 
may possibly be due to MDR1/BCRP intestinal inhibition. 
A limited risk of CYP induction could be expected in vivo. No induction CYP1A2 or CYP2B6 in 
any of the human hepatocyte donors tested when incubated by IVA337 (N=7) or its metabolites 
(N=3). A slight mRNA CYP3A4 induction was observed (2.3-12 fold, equating to 0.5-28 % of the 
response observed with rifampicin) at 12.5 µM while a mRNA repression was observed at higher 
concentrations. CYP3A4 enzyme activities (studied in four donors with IVA337) was shown to be 
slightly induced in two donors after incubation with IVA337 but only with high concentration 
(> 40 µM). 
No significant drug-drug interactions were observed with simvastatin and IVA337 (< 2-fold), and 
no PK/genotype (CYP450 isoenzymes and UGTs isoform) relationship has been identified. There 
was a 22% increase in Cmax and 39% increase in AUC of IVA337 in elderly subjects as compared 
to young subjects. 
 
1.4.3 
Toxicology 
IVA337 has a very low acute toxicity (maximal non-lethal dose of 2000 mg/kg in rodents) and is 

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not irritating to the skin. 
IVA337 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. 
IVA337 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  IVA337  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 IVA337 in rats and 
monkeys. 
No potential risks have been identified from pivotal toxicology studies with IVA337 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. 
The safety margins over expected human exposure in general toxicology studies were at least 20-
fold in rats and 3-fold in monkeys (Table 2). 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 3). 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. 
 
Table 2. 
Interspecies Comparison of Human and Animal Plasma Exposure to IVA337 
in General Toxicity Studies 
Human Plasma AUC at 
Species 
NOAEL 
AUC at NOAEL 
Safety Margin 
Estimated Active Dose 
Male-Female 
Male-Female 
(µg.h/mL) 
(mg/kg/d) 
(µg.h/mL) 
Mouse* 
25 
225 - 278 
~5 
50 
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 
 
Table 3. 
Interspecies Comparison of Human and Animal Plasma Exposure to IVA337 
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 

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3
 
Female 
105 ( 2.1) 
 
 
1 
values in brackets show exposure margin factor to clinical exposure 
 
 

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1.4.4 
Previous IVA337 Clinical Data 
IVA337 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 IVA337 after single increasing doses and after multiple increasing doses. The 
objectives of study S337.1.002 were to study the effect of IVA337 on the pharmacokinetics of 
simvastatin and simvastatin acid and to evaluate the pharmacokinetics of the two-crystalline 
anhydrous solid alpha and beta forms of IVA337. The objectives of study S337.1.005 were to 
assess the relative bioavailability of IVA337 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 IVA337 metabolites after single 
administration of 14C-IVA337. The objectives of study S337.2.001 were to evaluate the safety, 
tolerability, pharmacokinetics and pharmacodynamics of IVA337 in doses of 400 to 1200 mg daily 
over a 4-week period. The study IVA_01_337_HSSC_15_001 is a randomized, double- blind, 
placebo-controlled, multicenter proof-of-concept trial of IVA337 in the treatment of diffuse 
cutaneous systemic sclerosis (DcSSc). 
The study IVA_01_337_HNAS_16_002 is 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). 
In clinical trials performed in healthy volunteers and patients with type 2 diabetes, IVA337 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 treatment emergent 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, hemoglobin and 
hematocrit in healthy volunteers, and hypochromic anemia, 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 
1.5.1 
General Considerations 
This study is a Phase II randomized, double-blind, placebo-controlled, single-center, investigator 
initiated, 24-week treatment study of lanifibranor in adult subjects with T2DM and NAFLD. 
 
1.5.2 
Rationale for the Choice of Dose and Duration of Repeated Administration 
The evaluated treatment will be as tablets of lanifibranor 400 mg, one dose of lanifibranor, 800 mg 
once a day (QD) versus placebo, i.e. two tablets (lanifibranor or indistinguishable placebo) per os, 
once daily, for 24 weeks. To improve bioavailability, drug intake is combined with food. 
The dose has 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 and 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 in the clinic. 
Placebo is chosen as the comparator, as there is no licensed treatment for NAFLD/NASH. 
Treatment duration has been set to 6 months. This is a Phase II study and the aim to assess safety 
efficacy and mechanism of action. 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 (1, 23), suggesting that treatment efficacy can be observed early in the 
course of treatment. Significant effect on hepatic steatosis and necroinflammation has been 
reported before at 6 months with a PPARγ agonist (1). 
The study imposes 10 visits including the screen and follow-up visits and, apart 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 dyslipidemias can 
be treated with statins, which are allowed. 
Half of the patients is on verum treatment and can expect an improvement of their NAFLD and 
metabolic syndrome based on the results of previous clinical studies with PPARα, γ and α/δ 
agonists. The dose chosen for the trial demonstrated significant improvement in biomarkers of 
PPAR α, γ and probably δ in diabetic patients. 
 
Figure 3.        Phase IIa Biomarkers of IVA337 PPAR Activation in Diabetic Patients 
 
 
 
LS mean % change at D28 of Adiponectin 
 
Placebo 
400 mg IVA337 
800 mg IVA337 
1400 mg IVA337 

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2 
Investigators and Study Administrative Structure 
2.1 
Investigators and Other Participants 
The study will be performed in at the University of Florida (Endocrinology, Diabetes and 
Metabolism Division; and the Clinical Translational Research Institute), Gainesville, Florida. 
Principal Investigator: Pr. Kenneth Cusi, M.D., F.A.C.P., F.A.C.E. 
Professor of Medicine 
Chief, Division of Endocrinology, Diabetes and Metabolism 
The University of Florida 
1600 SW Archer Rd; room H -2 
P.O. Box: 100226 
Gainesville, FL 32610-0226 
Direct phone: 352-294-5723 
Division phone: 352-273-8662  
Co-investigators: 
Diana Barb, M.D. 
                  Romina Lomonaco, M.D. 
        Eddison Godinez Leiva, MD.  
      Troy Donahoo, M.D.  
      Julio Leey, MD  
      Other participants: 
Srilaxmi Kalavalapalli, Medical Scientist (Laboratory Director) 
Robert Campbell, Study Coordinator 
2.2 
Role of Inventiva SA and Representatives 
Inventiva SA will provide the treatment units and regulatory support to assist the Principal 
Investigator in the filling of an investigator-initiated IND. 
Inventiva SA will compensate the investigator and his institution for all study related costs. 
Inventiva S.A 
LS mean % change at D28 of HDL Cholesterol 
 
Placebo 
400 mg IVA337 
800 mg IVA337 
1400 mg IVA337 
 
 
400 mg IVA337 
800 mg IVA337 
1400 mg  IVA337 

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50 rue de DIJON, 21121 Daix, France 
Phone: +33 (0) 380 447 680 
Chief Medical Officer (CMO): Dr Michael Cooreman, MD 
Phone: +33 (0) 380 447 500 
Email:    michael.cooreman@inventivapharma.com. 
 
2.3 
Pharmacovigilance and Safety 
The Principal Investigator will ensure the safety of the study following GCPs and FDA regulations. 
 
2.4 
Other Relevant Institutions 
Cusi Lab 
1600 SW Archer Road Room R4-135 
Gainesville, FL 32610 
 
Shands Path Lab  
4800 SW 35th Drive 
Gainesville, FL 32608 
 
Product Manufacturing: 
DELPHARM, 10 rue Charbonneaux, 51100 Reims France 
Phone: +33 (0) 3 80 48 30 30 
Clinical Packaging: 
Amatsi group, 17 Rue des Vautes, 34980 Saint-Gély-du-Fesc, France 
Phone: +33 (0) 4 99 58 38 60 
 
3 
Ethical and Legal Considerations 
The principal investigator will obtain the approval of the study from the Competent Authority (CA) 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). The IRB 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 Principal Investigator will submit this protocol to the University of Florida IRB, and will 
forward to the Inventiva SA a copy of the written and dated approval (and annual reapproval) in 
order to allow delivery of the treatment units. 
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 approval. All correspondence with the IRB should be retained in the 
Investigator File. 
Investigational Medicinal 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 Principal 
Investigator and by Inventiva S.A. 

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3.2 
Protocol Amendments 
Inventiva S.A. will be informed of any change done by the Principal Investigator 
The change, presented as an amendment in written form to the protocol, will be signed by the 
Investigator and submitted to the IRB and whenever applicable to the CA for their approval. 
The amendment cannot be acted upon prior to the outcome of this decision. 
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 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 and Inventiva S.A. in writing immediately after the 
implementation. All updates to the Investigator’s Brochure, Protocol or any amendment-impacted 
documents will be sent to the IRB/IEC and CA whenever applicable. 
If requested, a progress report could be sent to the IRB 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 64th World Medical Assembly 
(Fortaleza, October 2013) and all applicable amendments laid down by the World Medical 
Assemblies, the guidelines of Good Clinical Practice CPMP/ICH/135/95 and applicable 
regulations, and any other relevant local requirement and laws. 
 
3.4 
Good Clinical Practice Responsibilities 
The responsibilities of the Principal Investigator will be as defined in the ICH GCP guidelines and 
applicable regulatory requirements. The Principal 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 Principal 
Investigator is aware of any information which might influence the evaluation of the benefits and 
risks of the IMP, Inventiva S.A. should be informed immediately. 
In addition, the Principal Investigator will inform Inventiva S.A. immediately of any urgency 
safety measures taken by the Principal Investigator to protect the study patients against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that the Principal 
Investigator becomes aware of. 
 
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 University of Florida has subscribed for itself and the Principal Investigator and 
the medical team working in the clinical trial to an insurance policy covering, in its terms and 
provisions, their 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 » 
 

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3.7 
Patient Information and Consent 
The Principal Investigator (according to applicable regulatory requirements), or a person 
designated 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 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 by Inventiva S.A. prior to submission to the appropriate IRB 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 Principal Investigator and Inventiva SA 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 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 is defined as the last visit (Visit 10, planned at the end of the 28-day off-drug follow- 
up period), of the last patient as defined in the protocol. 
 
4 
Study Objectives and Investigational Plan 
4.1 
Aim 
The primary aim is to establish the safety, efficacy and mechanism of action of lanifibranor in 
patients with NAFLD and T2DM. 
Specifically, to determine if lanifibranor decreases IHTG (primary endpoint), improves hepatic 
insulin sensitivity, endogenous (hepatic) glucose production, gluconeogenesis and de novo 
lipogenesis (DNL). This will be achieved by using a combination of intravenously infused stable 
isotopes and with the infusion of a low- and high-dose insulin infusion during a euglycemic 
hyperinsulinemic clamp (to quantify insulin action) with indirect calorimetry (to measure substrate 
oxidation). In addition, exploratory analysis with surrogate plasma biomarkers and imaging on 
changes on liver fibrosis with treatment will be performed. 
 
4.2 
Study Design 
The study is a two-arm (placebo, lanifibranor 800 mg/day), randomized (1:1), double-blind, 
placebo-controlled, 24-week treatment study. There is in addition a non-obese subject control 
group for the metabolic and imaging procedures. 
The study will require 32 ± 4 weeks (4-6 weeks for run-in, 24 weeks of treatment and 4 weeks 
post-study follow-up), with an estimated recruitment period of 6 to 9 months. 
Patients to be randomized: 34 allowing for a 10% drop-out rate. 
The overall study design is shown in Figure 1. 

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Study Duration and Procedures 
For each patient, the research study will be divided as follows: 
• Run-in period: Screening visit V1, DM medication titration V2, Baseline studies V3 and 
Randomization V4. 
• Interim V5 (4 weeks after V4), Interim V6 (8 weeks after V4), Interim V7 (12 weeks after 
V4), Interim V8 (16 weeks after V4), Interim V9 (20 weeks after V4). 
• Repeat baseline studies V10 (23 weeks after V4) and V11 (24 weeks after V4). 
• Off-drug Follow-up visit V12 (28 weeks after V4). 
 
4.2.1 
Screening Phase 
We plan to recruit patients with uncontrolled T2DM and a diagnosis of “fatty liver” per history 
(elevated AST/ALT and/or liver fat on liver ultrasound or ¹H-MRS and/or other appropriate 
imaging technique – see below). A Fibroscan study available in the research unit will be performed 
at the initial screen visit. 
CAP test (Fibroscan: ultrasound-based elastography available in the PI’s outpatient clinic and also 
research unit) will be performed at the initial screening visit to identify those patients with a fatty 
liver. 
The goal of the screening is therefore to check inclusion and exclusion criteria and adjust T2DM 
treatment as described below. 
Participants may be treated by diet only, or be on a stable dose of metformin and/or a sulfonylurea 
and/or a DPP-IV inhibitor for ≥ 2 months prior to enrollment. If the HbA1c is ≤8.0% on any of 
these diabetes medications, the dose of these medications will be kept stable throughout the study 
and baseline studies performed as outlined below. If the HbA1c is > 8.0% but ≤ 9.5%, metformin 
(minimum dose required: 1,000 mg/day for metformin) and/or a sulfonylurea (minimum dose 
required: glimepiride 2 mg once daily) will be added, or doses maximized, during the first 2 weeks 
of the lead-in period. The baseline visit to initiate lanifibranor (V4; Time 0 or randomization visit) 
will be not sooner than 8 weeks from diabetes medication titration and the patient should have an 
HbA1c ≤9.0% to proceed to randomization (V4). In addition, if both metformin and glimepiride 
(or another sulfonylurea) are already maximized at study entry (or the patient is intolerant to either) 
and the HbA1c ≥ 9.0% but ≤9.5%, we will add sitagliptin 100 mg daily (or an equivalent dose of 
another DPP-IV inhibitor) to reach an HbA1c ≤9.0% to proceed to randomization (V4). 
Afterwards, patient’s metformin and/or sulfonylurea dose and/or sitagliptin dose will be 
maintained at the new stable dose. The baseline visit to initiate lanifibranor (V0; Time 0 or 
randomization visit) will be not sooner than 8 weeks from diabetes medication titration and the 
patient should have a HbA1c ≤9.0% to proceed to randomization (V0). 
Of note, due to COVID-19 pandemic, in order to be able to accommodate the follow-up study 
procedures (i.e. liver MRI at V10 and insulin clamp at V11), for already enrolled subjects, treatment 
may have to be extended by one week up to no longer than 8 weeks. 
4.2.1.1 
Intrahepatic Triglycerides (IHTG) 
This will be the primary endpoint as assessed by ¹H-MRS (to be performed at Day -7). 
4.2.1.2 
Metabolic Studies 
As in prior trials by our group (1,2,9,10) to be done between Days -7 and 0. 
• Determination of hepatic insulin sensitivity, gluconeogenesis, and DNL. As described 
below, this will be done with use of labeled glucose, deuterium labeled water (D2O). 
Combined with a low- and high- dose insulin infusion during the euglycemic 
hyperinsulinemic clamp (to assess hepatic, muscle and adipose tissue insulin sensitivity) 
(see Appendix D) with standard stable isotopes to measure glucose and lipid turnover and 

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substrate oxidation (with indirect calorimetry). 
• Glycemic control: HbA1c (Day 0). 
• Biomarkers of adipose tissue metabolism (i.e., plasma adiponectin and adipokine panels 
measured by the gold-standard Millipore multiplex platform). (Day 0) 
4.2.1.3 
Surrogate Imaging and Plasma Biomarkers of Hepatic 
These will be measured by several techniques: 
• Vibration-controlled transient elastography (Fibroscan) (3): (Day-42) 
• Two-dimensional magnetic resonance elastography (MRE) (4). To be done during the 
IHTG ¹H-MRS measurement. To be done at Day -7. 
• T1 MRI mapping (5): To be done at Day -7. 
• Plasma biomarkers of liver fibrosis: Established (cytokeratin CK-18, plasma pro-C3 To 
be done between. Day – 7 and Day 0. 
4.2.1.4 
Genetic Markers 
Performed to assess potential subgroups (“responders”) to lanifibranor response (PNPLA3, 
TM6SF2, others). To be done at Day -7. 
4.2.1.5 
Description of Methods 
Liver ¹H-MRS , 2D-MRE and T1 MRI mapping: Between days -14 and 0, subjects will be 
invited to come to the National High Magnetic Field Laboratory at our university where the 3T 
magnet is located to have liver fat (IHTG) and liver fibrosis (by 2D-MRE and T1 MRI mapping) 
measured after at least a 3 hour fast. 
Admission for the determination of hepatic insulin sensitivity, gluconeogenesis, and de novo 
lipogenesis (DNL): Between Day -7 and 0 (to allow scheduling flexibility), subjects will be 
admitted to the research unit in the afternoon (4:00PM). Glucose and metabolism and DNL rates 
will be measured as reported in the literature before (1,2,9,10,12). In brief, patients will receive a 
standardized dinner and will fast overnight for at least 10 hours. Subjects will be given an oral 
dose (350 ml) of 70% deuterium labeled water (D2O), between 5 PM and midnight and prior to 
the metabolic experiments on the next day. After 6:00 PM, no calories or caffeine will be allowed 
until the end of the study on day 2. Non-caloric beverages will be allowed. 
If you are unable or unwilling to spend the night in the hospital, there is a possibility to perform 
this test without the overnight stay. You will still need to come to the CRC the day before the 
procedure at ~4:00 to 7:00PM to have a blood test done and receive the heavy water that you will 
drink at home (following the same instructions as if you were admitted). If you choose not to stay 
overnight you will need a driver the day of the procedure as the heavy water can produce some 
dizziness. 
The day of the procedure we will start at ~5:00-6:00AM. A bolus of [6,6-2H2] glucose (4.8 mg/kg 
body weight) will be given at 6:00 AM on day 2 followed by a constant infusion (0.08 mg/kg body 
weight/min) until the end of the study. Indirect calorimetry will be performed with a ventilated 
hood starting at 8:00 AM on day 2 and at regular intervals. Baseline endogenous glucose 
production (EGP) will be measured 150-180 minutes after starting [6,6-2H2] glucose to allow time 
for steady state enrichment of plasma glucose following standard principles of stable isotope 
dilution techniques. After baseline glucose and lipid turnover measurements, subjects will undergo 
a two-step euglycemic insulin clamp with a low- and high-dose insulin infusion combined with 
substrate oxidation determinations (i.e., indirect calorimetry) (see Appendix D). 
4.2.2 
Intervention Period (24 weeks) 
4.2.2.1 
Intrahepatic Triglycerides (IHTG) 
This will be the primary endpoint as assessed by ¹H-MRS (to be performed at V10). 

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4.2.2.2 
Metabolic Studies 
As in prior trials (1,2,6) to be done atV11. 
• Determination of hepatic insulin sensitivity, gluconeogenesis, DNL. As described below, 
this will be done with use of labeled glucose, deuterium labeled water (D2O). Combined 
with a low- and high- dose insulin infusion during the euglycemic hyperinsulinemic clamp 
(to assess hepatic, muscle and adipose tissue insulin sensitivity) with standard stable 
isotopes to measure glucose and lipid turnover and substrate oxidation (with indirect 
calorimetry). 
• Glycemic control: HbA1c, advanced lipid testing. (V11). 
• Biomarkers of adipose tissue metabolism (i.e., plasma adiponectin and adipokine panels 
measured by the gold-standard Millipore multiplex platform). (V11). 
4.2.2.3 
Surrogate Imaging and Plasma Biomarkers of Hepatic Fibrosis 
These will be measured by several techniques: 
• Vibration-controlled transient elastography (Fibroscan) (3): An established technique that 
allows to monitor fibrosis non-invasively at the bedside and outpatient setting. (V11). 
• Two-dimensional magnetic resonance elastography (MRE) (4). To be done during the 
IHTG ¹H-MRS measurement. To be done at V10. 
• T1 MRI mapping (5): A novel scanning protocol that allows for a complementary non- 
invasive measurement of liver fibrosis (in collaboration with the Oxford laboratory of R. 
Banerjee et al). To be done at V10. 
• Plasma biomarkers of liver fibrosis: Established (cytokeratin CK-18, HA, TIMP-1) and 
novel (pro-C3) plasma will be tested to gain insights into the role of treatment on liver 
fibrosis using surrogate markers of disease. To be done at V11. 
4.2.3 
Off-study Drug Follow-up Period (4 weeks) 
After all 24 week procedures, a 4-week safety period of observation will follow to ensure that 
patients are stable and the patient has a follow-up with their PCP and/or endocrinologist. 
4.2.4 
Patient Management at the End of Treatment 
The trial treatment is stopped after V11. 
After the follow-up, 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. 
If the study is positive there will be further trials for which these patients may be eligible. 
4.2.5 
Total Study Duration 
The total time (from first patient enrolled to last patient finished) will be 32±4 weeks (4-6 weeks 
for run-in, 24 weeks of treatment and 4 weeks post-study follow-up), with an estimated recruitment 
period of 32-40 weeks (conservatively set at ~1-2 patients per week, including about 30% of 
patients that will not qualify [n=16-20] and about 10 % dropouts/intolerant to lanifibranor that 
require additional recruitment [n=8]. 
Of note, due to COVID-19 pandemic, in order to be able to accommodate the follow-up study 
procedures (i.e. liver MRI at V10 and insulin clamp at V11), for already enrolled subjects, treatment 
may have to be extended by one week up to no longer than 8 weeks. After all procedures are 
completed and subjects are off drug, an additional 4-week safety period of observation will follow as 
specified in section 4.2.3. 
 

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4.3 
Study Population and Inclusion/Non-inclusion Criteria 
We propose to randomize 34 otherwise healthy overweight or obese patients with uncontrolled 
T2DM (HbA1c ≥ 6.0% to ≤ 9.5%) and NAFLD on imaging (see section 8). 
Ten healthy non-obese subjects without NAFLD will also be studied as “normal controls” for all 
the metabolic and imaging tests to be performed (V1, V3 and V4). We will study them only to 
examine the response of a person without diabetes to the study tests to be performed in the patients 
with type 2 diabetes who are participating in the clinical trial. In other words, they will be a 
“healthy control” to compare the results of blood tests, metabolic studies and imaging studies to 
be done in patients with diabetes participating in the study. Inclusion/Exclusion for the healthy 
controls will follow those noted in the protocol for patients with diabetes receiving treatment 
except that they will not have Type 2 diabetes based on a hemoglobin A1c and will be non-obese, 
BMI < 30 kg/m2. 
The diagnosis of NAFLD on imaging will be done by measuring intrahepatic triglyceride content 
(IHTG) using the gold-standard magnetic resonance and spectroscopy (¹H-MRS) technique. 
Pregnant women, prisoners, institutionalized individuals, or others who may be considered 
vulnerable populations will be excluded. The ethnic mix will reflect the base population in the 
North Florida/Alachua County area is 70-75% Caucasian, 15-20% African-American, 5-10% 
Hispanic, and 5% other ethnicities. We will only study otherwise healthy subjects with T2DM 
based on medical history, physical exam, and blood chemistries and hematologic tests. Body 
weight (≤ 5%) and physical activity should have been stable for at least 3 months. After informed 
consent has been obtained, each subject will undergo screening evaluations within the 4-6 weeks 
prior to the planned first double-blind study drug dose. Subjects may be eligible for randomization 
if the FPG ≥ 100 mg/dL and ≤ 250 mg/dL) at the Week -6 visit, and meet all other eligibility 
criteria (including Day -28 fasting fingerstick glucose ≥ 100 mg/dL and ≤ 250 mg/dL). 
 
 
4.3.1 
Inclusion Criteria 
1. Be able to communicate meaningfully with the investigator and legally competent to 
provide written informed consent 
2. Have an age between 21 to 75 years inclusive 
3. Subjects should be on stable standard of care and background therapy for ongoing chronic 
conditions, including stable doses of anti-diabetic medications, for at least two (2) months 
prior to trial entry 
4. Have uncontrolled diabetes with a fasting plasma glucose (FPG) ≥ 100 mg/dL but ≤ 250 
mg/dL and HbA1c ≥ 6.0% but ≤ 9.5%, on diet alone, or on metformin (≥1,000 mg/day), 
and/or sulfonylurea and/or DPP-IV therapy SGLT2 inhibitors. These medicines will be 
continued at stable doses during the entire study. 
• Subjects with an HbA1c > 8.0% but ≤ 9.5% will have their metformin (minimum dose 
required: 1,000 mg/day) maximized to 1,000 mg BID and/or glimepiride 2 mg once 
daily added during the first 2 weeks of the run-in period. The baseline visit to initiate 
lanifibranor (V4; Time 0 or randomization visit) will be not sooner than 8 weeks from 
diabetes medication titration and the patient should have an HbA1c ≤9.0% to proceed 
to randomization (V4). 
• In addition, if both metformin and glimepiride (or another sulfonylurea) are already 
maximized at study entry (or the patient is intolerant to either) and the HbA1c ≥ 9.0% 
but ≤9.5%, we will add sitagliptin 100 mg daily (or an equivalent dose of another DPP- 
IV inhibitor) to reach an HbA1c ≤9.0% to proceed to randomization (V4). 
5. Presence of hepatic steatosis (Intrahepatic Triglycerides [IHTG]) > 10 % determined by 
Magnetic Resonance and Spectroscopy (1H-MRS). 

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6. Have no new symptoms associated with decompensated diabetes in the previous three (3) 
months. 
7. Compensated liver disease with the following hematologic and biochemical criteria on 
entry into protocol: 
o Hemoglobin > 11 g/dL for females and > 12 g/dL for males 
o White blood cell (WBC) > 2.5 K/µL 
o Neutrophil count > 1.5 K/µL 
o Total bilirubin ≤ 1.3 mg/dL (≤ 22.2 µmol/L). Patients with bilirubin ≤ 1.3 mg/dL 
can be included if non-conjugated bilirubin in the setting of a Gilbert’s syndrome. 
o Albumin > 36 g/L 
8. No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, 
HCV, Wilson’s, α-1-antitrypsin deficiency, hemochromatosis, other). 
9. Negative pregnancy test or at least two-year 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 progesterone-containing) hormonal/ progesterone-only hormonal 
contraception associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomized partner). The 
contraceptive method will have to be followed for at least one menstruation cycle after the 
end of the study. 
 
4.3.2 
Non-Inclusion Criteria 
1. 
Evidence of liver disease other than NAFLD. 
2. History of excessive alcohol intake, defined by ≥ 21 units of alcohol per week in males and 
≥14 units of alcohol per week in females for two years prior to enrollment, where a “unit” 
of alcohol is equivalent to 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard 
liquor. 
3. Unstable metabolic condition: Weight change > 5% in the 3 months prior to enrollment, 
diabetes with poor glycemic control (HgbA1c > 9.5% or FPG > 250 mg/dl), introduction 
of an anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the 
past 6 months prior to screening. 
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. 
5. Subjects on sulfonylureas, metformin, GLP-1RA or DPP-IV unless the dose and body 
weight (within 5%) have been stable for at least two (2) months prior to study entry. 
6. Patients on insulin, pioglitazone (or prior use in the past 12 months). 
7. Patients on any of the following medications unless the patient has been on stable doses of 
such agents for the past two (2) months before entry into the study: thiazide or furosemide 
diuretics, beta- blockers, or other chronic medications with known adverse effects on 
glucose tolerance levels. Patients may be taking stable doses of estrogens or other 
hormonal replacement therapy if the patient has been on these agents for the prior two (2) 
months. Patients taking systemic glucocorticoids will be excluded. 
Patient on treatment with strong inducers or inhibitors of CYP2C8, or treatment with 
substrates of CYP2B6 or CYP2C8. When administered chronically, they should be 
replaced 2 months before the trial entry (See Inclusion criteria #3). If not administered 
chronically, they should be stopped at least 7 days before first dosing. 

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8. Patients with: 
a. History of myopathies or evidence of active muscle diseases 
b. Unstable cardiovascular disease, including: 
i. Unstable angina (i.e., new or worsening symptoms of coronary heart disease 
within the past 3 months), acute coronary syndrome within the past 6 months, 
acute myocardial infarction in the past 3 months or heart failure of New York 
Heart Association class (III-IV) or worsening congestive heart failure, or 
coronary artery intervention, within the past 6 months 
ii. History of (within prior 3 months) or current unstable cardiac dysrhythmias 
iii. Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or 
diastolic blood pressure > 100 mmHg. 
iv. Stroke or transient ischemic attack within the prior 6 months 
c. History of malignancy in the past 5 years and/or active neoplasm with the exception of 
resolved superficial nonmelanoma skin cancer 
d. History of bladder disease and/or hematuria or has current hematuria unless due to a 
urinary tract infection 
e. Any of the following laboratory values: 
i. Serum bilirubin > 1.3 mg/dL (or > 22.2 µmol/L). Patients with bilirubin > 1.3 
mg/dL can be included if non-conjugated bilirubin in the setting of a Gilbert’s 
syndrome. 
ii. Serum ALT > 3X ULN 
iii. INR > 1.2 
iv. Platelets < 150,000 per microliter of blood 
v. Renal impairment as demonstrated by estimated glomerular filtration rate 
(eGFR) < 60 mL/min/1.73m2 
vi. Total creatinine kinase > 1.5 X ULN 
vii. Lipase > ULN 
viii. Hemoglobin A1c > 9.5% 
9. Significant systemic or major illnesses other than liver disease, including those listed in 
exclusion criteria #8 and pulmonary disease, organ transplantation, serious psychiatric 
disease, that, in the opinion of the investigator, would preclude treatment with lanifibranor 
and/or adequate follow up. 
10. HB antigen > 0, HCV > 0 (patients with a history of HCV infection can be included if 
HCV PCR is negative since more than 3 years), prior history of HIV infection. 
11. Pregnancy/lactation or inability to adhere to adequate contraception in women of child-
bearing potential. 
12. Any other condition which, in the opinion of the investigator would impede competence or 
compliance or possibly hinder completion of the study. 
13. Body mass index (BMI) > 45 kg/m2. 
14. Type 1 diabetes and type 2 diabetic patient on insulin. 
15. Diabetic ketoacidosis. 
16. Fasting plasma triglycerides > 500 mg/dL. 
17. Hemostasis disorders or current treatment with anticoagulants. 
18. Participation in any other investigational drug study within the previous 3 months. 

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19. Have a known hypersensitivity to any of the ingredients or excipients of the IMP 
including: Lactose monohydrate, hypromellose, sodium lauryl sulphate, sodium starch 
glycolate, magnesium stearate, Opadry™ II 85F18422, DSS Granular, cellulose 
microcrystalline, maize starch. 
20. Be possibly dependent on the Investigator (e.g., including, but not limited to, affiliated 
employee). 
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. 
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. 
 
4.3.3 
Prohibited Concomitant Medications 
• PPAR gamma agonists, PPAR alpha agonists (fibrates), ezetimibe, 
• 
Bile salts chelators, Phytosterols, fish oils, 
• Insulin, 
• Vitamins E (alpha-tocopherol), 
• Anticoagulants (incl. warfarin, dabigatran, rivaroxaban, apixaban), 
• Systemic steroids (greater than physiological replacement of 30 mg of hydrocortisone or 
equivalent per day). 
• Substrates of CYP2B6 (e.g. artemether, artemisinin, bupropion, coumarins [e.g. warfarin, 
acenocumarol], cyclophosphamide, efavirenz, ifosfamine, mephobarbital, methadone, 
nevirapine, pethidine, propofol, selegiline). However, if medically necessary, these 
treatments can be administered for a single intake, occasionally.  
• Substrates of CYP2C8 (e.g. amodiaquine, clopidogrel, daprodustat, dasabuvir, 
enzalumatide, montelukast, paclitaxel, repaglinide, torasemide). However, if medically 
necessary, these treatments can be administered for a single intake, occasionally.  
• CYP2C8 strong inducers (e.g. pentobarbital, phenytoin, rifampin, rifamycin, 
secobarbital). However, if medically necessary, these treatments can be administered for a 
single intake, occasionally.  
• CYP2C8 strong inhibitors, when systemically administered, i.e. by oral, intra-venous or 
intra-muscular route of administration (e.g. gemfibrozil, clopidogrel, felodipine, 
zafirlukast, candesartan celixetil, ketoconazole). 
 
Allowable medications for standard care or precautions: 
• Obesity: stable weight defined by no more than a change of >5% in the 3 months prior to 
enrollment (see exclusion criteria N° 3). 
• Treatment used for the underlying medical conditions: 
Treatments are allowed within certain restrictions (described above and below) and 
provided that they have been kept at stable doses for at least 2 months before inclusion  
in the study. 
o Type 2 diabetes: 

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• Metformin, 
• Sulfonylureas, 
• Dipeptidyl peptidase-4 inhibitors, 
• Sodium-glucose transport protein 2 inhibitors: canagliflozin, dapagliflozin 
and empagliflozin. 
o Hyperlipidemia: only statins at stable doses will be allowed. 
o Antiplatelets agents: The antiplatelets agents (incl. low-dose aspirin, ticlopidine, 
clopidogrel, prasugrel, ticagrelor) are allowed. 
o Herbal supplements: 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 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 Principal Investigator about the concomitant medication 
given. 
4.3.4 
Enrollment 
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. 
 
 
4.4 
Study Medication 
4.4.1 
Identity of Investigational Medicinal Product(s) (IMP) 
The lanifibranor tablets and placebo to match (PTM) are white to off-white, oval 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 (4-[1-(1,3-benzothiazol- 
6-ylsulfonyl)-5-chloro-1H-indol-2-yl]butanoic acid). 
• The placebo tablet contains a physical mixture of lactose monohydrate, microcrystalline 
cellulose, and pre-gelatinized starch and magnesium stearate. 
 
4.4.2 
Treatments Administered 
This double blinded placebo-controlled study involves a therapeutic dose of 800 mg lanifibranor 
(QD). 
The lanifibranor tablets and PTM are packaged into round high-density polyethylene (HDPE) 
bottles containing 38 tablets for a treatment period of one month, plus a use margin of 1 week with 
proper closures fitted with a silicagel cartridge. Two bottles each (either active or placebo) are 
assembled in a carton to compose monthly Kits as detailed below: 
• Placebo Kit: Morning (P+P) 
• 800 mg Kit: Morning (A+A) 

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Where P denotes the placebo tablet and A denotes the active tablet (400 mg). 
A total of 6 monthly patient kits (2 HDPE Bottles of 38 tablets each) is representing the treatment 
per patient for the clinical study. 
 
4.4.3 
Medication Dispensing 
4.4.3.1 
Medication Dispensing 
The patients receive 3 monthly patient kits at V4 and 3 monthly patient kits at V6. They are 
instructed to take morning 2 tablets with food, i.e. one tablet from either the one of the two 
containers. The overall treatment duration is 24 weeks. However, due to COVID-19 pandemic, in 
order to be able to accommodate the follow-up study procedures (i.e. liver MRI at V10 and insulin 
clamp at V11), for already enrolled subjects, treatment may have to be extended by one week up to 
no longer than 8 weeks. Additional medication dispensing, if necessary, will be done as part of an 
unscheduled follow-up visit. 
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 any dosage 
modifications by the patient are documented in the eCRF. 
 
4.4.4 
Selection and Timing of Dose for Each Patient 
Patients will be randomized equally 1:1: to either dose of lanifibranor or placebo. 
The randomization list will be setup with blocs of size equal to 4. 
The randomization list will be produced by a statistician of Keyrus Biopharma according to their 
SOPs and will be used to prepare the medication accordingly. Each eligible subject will be 
randomized to placebo or lanifibranor according to the randomization scheme at the time of 
randomization visit (V4). 
Treatment numbers will be allocated in ascending order using the next available consecutive 
number. 
One copy of this list will be sent to the company responsible for manufacturing and labelling of 
the treatment (AMATSI) and another blind copy will be sent to the investigator. These copies will 
be stored in confidential manner up to the unblinding after database lock. 
The blind copy will contain three additional columns and the investigator will have to complete 
the columns “Randomization date”, “Patient number” and “Investigator initials” after each 
randomization. 
Two separate sealed envelopes (one for the investigator, one for STRAGEN) will be prepared by 
Keyrus Biopharma. These individual envelopes will contain the identity of the study medication 
allocated to the patient in case of emergency (see §9.2.1). 
 
4.4.5 
Labeling 
Packaging and labeling is performed by Amatsi group, 17 Rue des Vautes, 34980 Saint-Gély-du- 
Fesc, France Phone: +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. 
 
Table 4. 
Summary of Labeling Details 
 
 
Caution: New Drug--Limited by Federal (or United States) law to investigational use. 
 
 
Investigator site 
Division of Endocrinology, Diabetes and Metabolism 

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The University of Florida 
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: 
Lanifibranor /2018 
 
 
Principal Investigator: 
Kenneth Cusi, M.D. 
 
 
Direction for Use: 
Take 2 tablets by mouth once daily with food (morning), from either one of 
the two bottles. 
 
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. 
Keep Out of Reach of Children. 
 
 
 

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4.4.6 
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 destruction, 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. 
 
4.4.7 
Treatment Compliance 
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. 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 by the Site Coordinator and recorded in the eCRF 
 
4.4.8 
Return or Destruction of Investigational Products 
The products are collected by the Principal Investigator at the end of the study and are thereafter 
destroyed. 
 
 
5 
Measurements Assessed and Study Flow Chart 
The following section presents the assessments performed at each visit. Target dates are ±5 days 
compared to V1. 
 
5.1 
Table of Study Procedures and Assessments 
A table is provided in the Schedule of Study Procedures (Table 1). 
 
 
5.2 
Specific Procedures for Assessment of Outcomes 
Safety laboratories should be monitored by a central laboratory in real time with potential DILI 
alerts sent to the investigator. 
If patient lives in a remote area, testing can be performed locally and the results communicated to 
the investigator site promptly. 
5.2.1 
Urine Samples 
Urine Samples will be collected at V1, V11 and V12. 
Urine Pregnancy test will be performed at V1, V4, V7, V9, V11 and V12. 
Urine specimens will be obtained by providing participants with a collection cup and instructions 
for collecting as described in the sampling kit supplied by the hospital laboratory. 
Safety assessments may be performed on the urine samples in case of renal function impairment 
is observed during the study. Increase of 50 % or 1.5. Albuminuria and other biomarker like 
cystatin C will be tested, and aliquots of urine samples will be stored in case where a urine 

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biomarker specific of NAFLD would be 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 hospital laboratory at the end of a scheduled storage 
period (1 year after the end of the study). 
 
5.2.2 
Blood Samples Taken 
Blood sample taken are performed at V1 (screening), V4 (randomization), V5, V6, V7, V8, V9, 
V11 and V12 (Follow-up). 
Total blood volume sampled during the study for each patient (for, biomarkers, safety and efficacy 
biological tests) will be as follows: 
 
Table 5. 
Blood Volume Taken at Each Visit per Type 
 
(ml) 
 
 
SST 
 
 
Serum 
(red) 
 
 
EDTA 
(whole 
blood) 
 
 
EDTA 
(plasma) 
Citrate 
Fluoride 
Li Hep 
Glucose 
ANALOX 
 
 
Total 
(ml) 
 
 
 
OVERALL TOTAL: 471.5 ml 
Attention must be paid to the kind of blood sample required as they vary between visits. 
For the monitoring of the individual subject, each sample 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. 
All blood samples will be destroyed by the laboratory at the end of a scheduled storage period (1 
year after the end of the study). 
 
5.2.3 
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: Methods and Normal Values for Vital Signs, 
Waist and ECG). 
 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
5 
5 
5 
1.8 
6.8 
1.8 
1.8 
1.8 
1.8 
1.8 
6.8 
6.8 
2 
2 
2 
2 
2 
2 
2 
2 
2 
154 
6 
154 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2.7 
2 
2 
2 
6 
3 
3 
3 
6 
3 
25 
25 
19.5 
198.5 
9.5 
4.5 
15.5 
4.5 
4.5 
203.5 
11.5 

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5.2.4 
Electrocardiogram 
12-lead ECGs will be performed at Screening (V1), and the end-of-treatment visit (V11). 
 
5.2.5 
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. 
 
5.3 
Procedures at Each Visit 
5.3.1 
Screening (V1) 
The Principal Investigator invites the potential patients to participate to the study according to the 
patient’s medical records. Both will go through the informed consent and the Principal Investigator 
answers to any question the patient would have. 
The patient is given enough time to discuss his/her participation to the study with his/her family, 
friends and family doctor. 
The patient is asked to date and sign the “Informed consent form”, prior to any study procedure. 
Screening (V1) procedures are listed on the “Study Schedule of Procedures”. (see Table 1) 
Medical history including concomitant medication is reviewed. 
Physical examination (vital signs, weight, height and waist measurement) is performed. 
12-lead ECG, routine chemistries (CBC, CMP, lipids, CPK, CPK-MB, HbA1c) and urinalysis 
(including urine pregnancy test) are performed. 
TSH, free T4, not necessary if available within the past 12 months. 
Fibroscan procedures: CAP and VCTE are performed. 
In subjects with abnormal labs, baseline measure (BLM) should be determined by 2 separate 
measurements obtained approximately approximately 4 weeks apart. To be eligible for study entry, 
the differences in the levels of those repeat measures of baseline serum AST, ALT, ALP, and total 
bilirubin should be small (<20%). 
Subjects with an HbA1c > 8.0% but ≤ 9.5% will have their metformin (minimum dose required: 
1,000 mg/day for metformin) maximized to 1,000 mg BID and/or glimepiride 2 mg once daily 
added during the first 2 weeks of the run-in period. 
In addition, if both metformin and glimepiride (or another sulfonylurea) are already maximized at 
study entry (or the patient is intolerant to either) and the HbA1c is ≥ 9.0% but ≤9.5%, sitagliptin 
100 mg daily (or an equivalent dose of another DPP-IV inhibitor) will be added. 
All patients on concomitant anti-diabetic medications should have, or be provided with, a glucose 
monitor and instructions for its use. Fasting blood glucose and spontaneous measurements in the 
event of suspected hypoglycemia should be routinely monitored by the patient and values should 
be recorded (in their glucose monitoring device or diaries) to be discussed at each visit with study 
staff. Patients will be instructed on actions to take in the event of hypoglycemia in accordance with 
standard of care. 
Finally, eligibility criteria are reviewed and if the patient is eligible, the next visit should take place 
within 2 weeks +/- 5 days. 
 
 

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5.3.2 
Medication Titration (V2) at Week -4 
The assessments performed are listed on the “Study Schedule of Procedures” (see Table 1). 
The key procedure at this visit is the DM medication titration done by staff, with assessment 
including a fasting fingerstick glucose procedure. 
AEs, if any occurred since the previous visit, are reported. Please refer to section 6 for AEs 
reporting. 
 
5.3.3 
Baseline Visit (V3) at Week -1 
The procedures are listed on the “Study Schedule of Procedures” (see Table 1). 
Liver imaging: liver fibrosis (MRE) and T1 MR mapping and liver IHTG content are performed. 
AEs, if any occurred since the previous visit, are reported. Please refer to section 6 for AEs 
reporting. 
 
5.3.4 
Randomization Time 0 (V4) 
The assessments to be performed are listed on the “Study Schedule of Procedures”. (see Table 1) 
At this visit, the eligibility of the patient is confirmed (inclusion/exclusion criteria). 
Patient will be admitted to the CRC (clinical research unit) including overnight stay. 
Inpatient metabolic testing will be performed: insulin sensitivity study, DNL and GNG. 
Blood sampling using kits and instructions provided will be done for safety and efficacy purposes. 
Blood samples will be taken in the morning after overnight fasting. The patient must be fasting 
overnight from 10:00 pm. 
AEs, if any occurred since the last visit, are reported. Please refer to section 6 for AEs reporting 
Concomitant medications are also reported. 
The patients are then randomized and receive 3 monthly patient kits of medication. Each kit will 
contain 2 bottles. Each kit contains 4-weeks plus 1-week margin of tablets. 
Patients are carefully instructed to take morning 2 tablets with food, i.e. one tablet from either 
container. 
Patients are also carefully instructed to come back to the site in case of symptoms of dyspnea, 
edema, or a presumptive diagnosis of heart failure. NT-proBNP should be measured as close to 
the event as possible. They will also be instructed to call the investigator in case of new or 
worsening symptoms of clinical hepatitis, including loss of appetite, fatigue, mild fever, muscle or 
joint aches, nausea and vomiting. This will be reminded to them at each subsequent visit. Patients 
and caregivers accompanying them during the study visits will receive education for potential 
symptoms of adverse effects that should be reported to the investigators, such as skeletal muscle 
pain, weight gain, peripheral edema, shortness of breath, or new or worsening symptoms of clinical 
hepatitis (RUQ pain, dark urine, extreme fatigue, nausea and vomiting), mild fever, etc. These 
will be asked and recorded at each visit. 
Important is to remind the patients, to bring back the unused medication at each visit. 
 
5.3.5 
Follow-up Visits (V5) at Week 4, (V6) at Week 8, (V7) at Week 12, (V8) at Week 
16 and (V9) at week 20 
The assessments to be performed are listed on the “Study Schedule of Procedures”. (see Table 1) 
Please note that the follow-up visits are not at regular intervals and the assessments vary from one 

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visit to the next. 
Blood sampling using kits and instructions provided will be done for safety and efficacy 
purposes.If subjects develop elevations of AST or ALT > 2 times baseline measure or total 
bilirubin > 1.5 times BLM while on study, testing should be repeated within 48 to 72 hours. 
Persistent elevations should be followed by repeat testing and physical examination 2-3 times per 
week with or without drug discontinuation. 
AEs, if any occurred since the previous visit, are reported. Please refer to section 6 for AEs 
reporting. At each visit, the investigator will ask the patients on the occurrence of skeletal muscle 
pain or joint aches, peripheral edema, shortness of breath, loss of appetite, fatigue, mild fever, 
nausea and vomiting since last visit. 
Concomitant medications are recorded. 
If 2 months after randomization, i.e. (V6) at Week 8, sitagliptin 100 mg/day will be added the 
HbA1c exceeds ≥9.5%. If the subject is already on sitagliptin (or an equivalent dose of another 
DPP-IV inhibitor), or has a history of intolerance to DPP-IV inhibitors, bedtime long-acting insulin 
Lantus at 0.3 units/kg will be started and titrated aiming to keep the fasting plasma glucose below 
120 mg/dL. If at 4 months, i.e. (V8) at Week 16, the HbA1c remains ≥9.5% and the patient is 
already on maximal doses of metformin, sulfonyurea and sitagliptin, as well as on insulin, the 
patient will be discontinued from the study due to non-adherence to therapy. 
At V7, patient receives 3 monthly patient kits of medication. Each kit will contain 2 bottles. Each 
kit contains 4-weeks plus 1-week margin of tablets. 
For affected subjects due to COVID-19 pandemic, in case drug treatment has to be extended for 
1-8 weeks, additional safety labs (CBC, CMP, CK, and lipase) if not available in the past 8 weeks, 
will have to be re-collected prior to the treatment extension. Additional medication dispensing if 
needed will be performed in an unscheduled visit. If any adverse reaction occur during this period 
patient will be seen in an unscheduled visit as needed. 
5.3.6 
Repeat Baseline Studies (V10) at Week 23 and at (V11) at Week 24 
The assessments to be performed are listed on the “Study Schedule of Procedures” (see Table 1). 
The assessments are different in V10 and V11 (see below). 
Blood sampling using kits and instructions provided will be performed for safety and efficacy 
purposes. 
Key procedures at each visit are the following: 
At (V10) liver imaging: liver fibrosis (MRE) and T1 MR mapping and liver IHTG content are 
performed. 
At (V11) patient will be admitted to the CRC (research unit) including an overnight stay. 
Inpatient metabolic testing is performed: including HbA1c, insulin sensitivity study, DNL and 
GNG. 
AEs, if any occurred since the previous visit, are reported. Please refer to section 6 for AEs 
reporting. 
Concomitant medications are recorded. 
As already noted, due to COVID-19 pandemic, for already enrolled subjects, the liver MRI at V10 
and insulin clamp at V11 may have to be completed out of window by one week and up no longer 
than eight weeks. 
 
5.3.7 
Off-Drug Follow-up (V12) at Week 28 
This last patient’s visit includes: concomitant medications and AEs reporting, vital signs, routine 

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chemistries, urinalysis and urinary pregnancy test among other assessments. 
All the assessments to be performed are listed on the “Study Schedule of Procedures”. (see Table 
1). 
For those subjects where the course of the study was affected by the COVID-19 pandemic, and 
treatment was extended for no longer than 1-8 weeks, the final off-drug follow-up visit 12 will be 
performed 4 weeks after stopping the study drug. 
 
5.3.8 
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 below will automatically generate an unscheduled/safety visit: 
- 
If patients develop elevations of AST or ALT > 2 times baseline measure or total bilirubin 
> 1.5 times BLM while on study, testing should be repeated within 48 to 72 hours. 
Persistent elevations should be followed by repeat testing and physical examination 2-3 
times per week with or without drug discontinuation. 
- 
If a patient has symptoms of dyspnea, edema, or a presumptive diagnosis of heart failure, 
NT-proBNP should be measured as close to the event as possible. 
- 
Asymptomatic subjects with lipase values above 1.3X ULN (if not on a DPP-IV inhibitor) or 
>2.0X ULN if taking a DPP-IV  inhibitor, will be retested within 7 days without drug 
interruption. Should retest values return to below inclusion criteria, the drug may be 
continued. If retest values are > ULN or the subject becomes symptomatic, they should be 
discontinued from drug. 
Please also refer to section 9.1 for patient withdrawal criteria. 
6 
Safety Assessment 
6.1 
Adverse Events 
All adverse events (AEs), regardless of severity or potential relationship to study drug, will be 
recorded using medical terminology in the source document and the eCRF 
6.1.1 
Definitions 
• Adverse event: Any untoward medical occurrence in a patient administered the 
investigational medicinal product (IMP) and which does not necessarily have a causal 
relationship with the IMP. An adverse event (AE) can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the IMP, whether or not considered related to the 
IMP. 
• Suspected adverse reaction: Any AE for which there is a reasonable possibility that the 
IMP caused the AE. All untoward and unintended responses to the IMP related to any dose 
administered. All AEs judged by the investigator as having a reasonable causal relationship 
(i.e. unlikely, possible or probable) to the IMP qualify as suspected adverse reactions. The 
expression “reasonable causal relationship” means there is evidence to suggest a causal 
relationship between the IMP and the AE. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by 
the IMP. 
 
 

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6.1.2 
Collection 
The condition of the patients will be monitored throughout the study. 
Any AE (including laboratory test abnormalities, patient’s subjective symptoms, intercurrent 
illnesses or injuries, and/or study procedures-related AE) reported spontaneously by the patients, 
or observed by the investigator or medical staff, will be recorded in the source records and the 
eCRF. 
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. An AE includes: 
A clinically relevant worsening of an existing illness and/or a clinical laboratory adverse event 
(CLAE): a laboratory abnormality that is clinically significant and suggests toxicity of a magnitude 
that requires active management (either active treatment or more clinical investigations, such as 
more frequent follow-up to monitor the abnormality. 
The following are not to be reported as AEs: 
- Pre-existing conditions found at screening or before exposure to trial drug: they should be 
included instead in the medical history or concomitant procedures. 
- Non-severe hypoglycemia is to be considered an AE, but will be reported under 
hypoglycemic episodes forms rather than in the eCRF AE forms. 
- Pre-planned procedures, unless the condition for which the procedure was planned has 
worsened since the participant has signed the informed consent form 
6.1.3 
Intensity Rating 
- 
The 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE: 
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06- 
14_QuickReference_5x7.pdf ) will be used for reporting AEs. 
The intensity of an AE will be rated as follows: 
- 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
- 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental Activities of Daily Living (ADL) (preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.) 
- 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden) 
- 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
- 
Grade 5 Death related to AE. 
Mild: no interference with the patient’s daily activities and does not require mandatory 
corrective/symptomatic treatment. 
- 
Moderate: moderate interference with the patient’s daily activities and/or requires minimal 
medical intervention or corrective treatment required. 
- 
Severe: major and unacceptable interference with the patient’s daily activities and requires 
mandatory corrective/symptomatic treatment, possible hospitalization. 
 
 

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6.1.4 
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. 
6.1.5 
Action Taken 
The action taken with the IMP for an AE will be rated as IMP 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. 
6.1.6 
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. 
 
Definitions: 
- 
Recovered/resolved: The subject has fully recovered, or by treatment of some sort the 
condition reported has now returned to the level observed at the first trial-related activity 
after the subject signed the informed consent. 
- 
Recovering/resolving: The condition is improving and subject expected to recover from 
the mentioned event. 
- 
Recovered/resolved with sequelae: The subject has recovered from AE but with lasting 
effect due to a disease, injury, treatment or procedure. 
- 
Not recovered: The condition has not improved or the symptoms are unchanged. Also, if 
the outcome is unknown. 
- 
Fatal: To be used only if the subject has died from the condition/reported adverse event. 
An AE with fatal outcome must be reported as an SAE. 
- 
Unknown: There is no available information related to the condition of the AE. 
6.1.7 
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. 
6.1.8 
Worsening Signs 
Symptoms, syndromes or diagnoses present before the first IMP administration will be considered 
as AEs if they worsen after the start of the IMP. 

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6.2 
Serious Adverse Events 
6.2.1 
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: a 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 the eCRF in the medical history or concomitant procedures page. 
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 judgment, 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. 
 
Other events for immediate reporting 
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 
in an expedited manner with the same procedure and timelines as for SAEs (see section 6.3.1), 
independently from the occurrence of an AE. 
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 reported in an expedited manner with the same procedure and timelines as for SAEs (see section  
6.3.1), independently from the occurrence of an AE. Specific follow-up of the event will be done 
by the investigator until pregnancy outcome, following standard procedures established by the 
University of Florida Institutional Review Board (IRB). 
 
6.3 
Reporting requirements 
6.3.1 
Immediate reporting 
The investigator will immediately, i.e. within 24 hours from first knowledge, report any SAE 

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occurring during the study to the appropriate Data Safety Monitor Board (DSMB) and IRB that 
approved the protocol. 
The investigator will complete sign a SAE Report Form and transmit it to the DSMB and IRB by 
email or telefax not later than 24 hours after the first knowledge of the SAE. The DSMB and IRB 
acknowledge the receipt of the SAE information by email to the investigational site within one 
working day (unless on a weekend or Holiday when reporting will occur on the first working day). 
In the absence of email acknowledging the receipt, or in case of any issue in sending the fax or 
email, the investigator shall contact the DSMB and IRB by any means for ensuring the receipt of 
SAE information at the earliest opportunity. 
Any follow-up information will be reported to the DSMB and IRB as soon as it becomes known, 
with the same process and timelines as described here above for initial reports. 
SAEs 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. 
6.3.2 
IND safety reporting requirements 
The investigator will be responsible for the declaration of suspected unexpected serious adverse 
reactions (SUSARs) according to US FDA regulation. Expectedness will be based on the safety 
reference document i.e. the Investigator Brochure (IB). 
6.3.3 
Reporting to Inventiva SA 
Inventiva SA, through its new pharmacovigilance contractor, United BioSource Corporation 
(UBC), will be copied on all SUSAR and SAE declarations and will collect in its safety database 
UNITED BIOSOURCE CORPORATION 
Email: Inventivasafety@ubc.com 
UBC will ensure that appropriate cross-reporting of SUSAR originating from the present 
clinical trial is performed in all countries with on-going lanifibranor trials. 
6.3.4 
Cross-reporting 
SUSAR and SAE’s occurring from other on-going lanifibranor trials will be sent by Inventiva SA, 
through its pharmacovigilance contractor, UBC, to the investigator for reporting to local 
competent authorities in accordance with local regulation. 
 
6.4 
Safety Variables 
All safety variables will be primary ones. Safety evaluations will be completed as given in section 
8.7 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. 
Safety endpoints 
Secondary safety endpoints will be used to support the safety objectives of the study, such as the 
number of treatment-emergent adverse events, including hypoglycemic episodes (i.e., blood- 
confirmed glucose levels below 40 and 70 mg/dL, severe symptomatic hypoglycaemic episodes 
during the trial), as well as haematologic and biochemical tests as described in Table 6 below. 
Hypoglycaemic episodes will be classified and then summarized as: a) Number and percentage of 
subjects with at least one event; b) Total number of events and per ADA category (see below); and 
c) Event rate per 100 patient years of exposure. 
The study will use the ADA classification/criteria of hypoglycaemia as follows (35): 

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• Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
• Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 70 mg/dL. 
• Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 70 mg/dL. 
• Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of 
the typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 
70 mg/dL but approaching that level. 
• Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 70 mg/dL. 
 
6.4.1 
Physical Examination 
Physical examinations will be conducted by the investigators. Any findings will be documented in 
the source document and recorded in the eCRF. 
 
6.4.2 
Laboratory Tests 
Laboratory tests will be analyzed mainly at the hospital laboratory. 
Additional samples for laboratory safety variables may be drawn at any time during the study at 
the investigators judgment. The laboratory assessments performed at each visit are listed in the 
following table (see Table 6). 
 
Table 6. 
Laboratory Tests 
WEEK 
- 6 
-4 
-1 
0 
4 
8 
12 
16 
20 
23 
24 
28 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
TEST 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Blood Count 
RBC count 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Haemoglobin 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Haematocrit 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
WBC count 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
WBC Differential 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Platelet count 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Comprehensive metabolic profile 
Fasting Plasma Glucose 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Electrolytes 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Albumin 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Total protein 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Calcium 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 

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WEEK 
- 6 
-4 
-1 
0 
4 
8 
12 
16 
20 
23 
24 
28 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
TEST 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
AST  
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
ALT 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Alkaline Phosphatase  (ALP) 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
INR 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Serum creatinine and eGFR 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Lipase  
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Lipids 
Total Cholesterol 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
HDL-C 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
LDL-C 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Non-HDL-C 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Triglycerides 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
CPK and CPK-MB 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
HbA1C 
X 
 
X* 
X 
 
X 
 
X 
 
 
X 
X 
 
TSH, Free T4 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy test 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
FSH 
(postmenopausal 
patients only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Outcome Laboratories 
Fasting Plasma Glucose 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
Fasting Fingerstick glucose 
 
X 
 
 
 
 
X 
 
 
 
 
 
Advanced 
lipid 
panel 
(lipoproteins, particle # size) 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Exploratory 
biomarkers 
(hsCRP, IL-6, TGF-beta) 
 
 
 
X 
X 
 
X 
 
 
 
X 
 
Adiponectin 
 
 
 
X 
 
 
X 
 
 
 
X 
 
ProC3 (Nordic) 
 
 
 
X 
 
 
X 
 
 
 
X 
 
*Only if the dose of diabetes medications has been changed after enrollment 
 

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WEEK 
- 6 
-4 
-1 
0 
4 
8 
12 
16 
20 
23 
24 
28 
VISIT 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
TEST 
 
 
 
 
 
 
 
 
 
 
 
 
CK-18 
 
 
 
X 
 
 
 
 
 
 
X 
 
Genotyping (SNPs of 
interest) 
 
 
 
X 
 
 
 
 
 
 
 
 
Inpatient metabolic testing 
Insulin sensitivity study  
 
 
 
X 
 
 
 
 
 
 
X 
 
Rates of novo lipogenesis 
(DNL) and gluconeogenesis 
 
 
 
X 
 
 
 
 
 
 
X 
 
Indirect calorimetry 
 
 
 
X 
 
 
 
 
 
 
X 
 
Urine 
collection 
for 
metabolic measurements 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
6.4.3 
Vital Signs 
Vital signs will be assessed at each visit including the screening visit and from V1 to V4. Please 
refer to section 5.2.5 for the detailed technical procedure. For methods and normal values 
definition, see Appendix B: Methods and Normal Values for Vital Signs, Waist and ECG. 
 
6.4.4 
Electrocardiogram 
Please refer to Appendix B: Methods and Normal Values for Vital Signs, Waist and ECG for the 
detailed technical procedure. 
 
6.5 
Data Safety Monitoring Committee 
Below is the list of members of the DSMB for the lanifibranor clinical trial. They will meet on a 
quarterly basis and monitor for protocol deviations, adverse events and review any serious 
adverse events. 
 
Chair: 
Steve Anton, Ph.D. 
Associate Professor & Clinical Research Division Chief 
Department of Aging and Geriatric Research 
Department of Clinical and Health Psychology 
College of Public Health and Health Professions 
College of Medicine, University of Florida 
Gainesville, FL 32611 
Phone: 352-273-7514 
Fax: 352-273-5920 
 
Members: 
Roberto J. Firpi, M.D., M.S., AGAF, FAASLD, FACG 
Associate Professor of Medicine 
University of Florida 
Section of Hepatobiliary Diseases and Transplantation 

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Department of Medicine 
1600 SW Archer Rd, MSB Room M440 
Gainesville, FL, USA 
Phone: 352-273-9466 
 
Maryam Sattari, M.D. 
Clinical Associate Professor of Medicine 
University of Florida 
Department of Medicine, Division of Internal Medicine 
1600 SW Archer Rd 
Gainesville, FL, USA 
Phone: (352) 265-0140 
 
Juan Manuel Muñoz Pena 
Assistant Clinical Professor 
Division of Endocrinology, Diabetes and Metabolism 
Department of Medicine 
1600 SW Archer Rd 
Gainesville, FL, USA 
Phone: (352) 273-8656 
 
Margaret C. Lo, MD FACP 
Associate Professor of Medicine 
Associate Program Director, UF Medicine Residency Program 
Program Co-Director, VA Chief Residency in Quality Safety 
Director, UF Primary Care Track 
Department of Medicine, Division of Internal Medicine 
University of Florida College of Medicine 
Gainesville, FL 32610 
(352) 265-0651 (office) 
(352) 265-0239 (residency office) 
(352) 265-0153 (fax) 
 
Verification according to University of Florida standards for clinical trials. 
All data must be verifiable in source documentation other than the eCRF. 
 
 
7 
Data Quality Assurance 
7.1 
Monitoring 
The PI and Medical staff will verify during monitoring visits, the monitors will verify the 
adherence to the protocol, the maintenance of all study-related records and the accuracy and 

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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 appropriate 
regulatory authorities’ direct access to source documents to perform the verification according to 
University of Florida standards for clinical trials. All data must be verifiable in source 
documentation other than the eCRF. 
The study sites may be subject to review by the Institutional Review Board (IRB)/Data Safety and 
Monitoring Board (DSMB), and/or to quality assurance audits, and/or to inspection by appropriate 
regulatory authorities. The collection and processing of personal data from subjects enrolled in this 
study will be limited to those data that are necessary to fulfill the objectives of the study. 
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 
process. 
 
7.2 
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. We 
will 
use 
a 
program 
called 
REDCap™ 
(Research 
Electronic 
Data 
Capture; 
https://www.ctsi.ufl.edu/research/study-design-and-analysis/redcap). It is a secure, Web-based 
application designed to support traditional case report form data capture for research studies 
performed at NIH-based Clinical Translational Science Institutes (CTSIs) use. It is a flexible 
platform that allows Export data to Microsoft Excel and statistical packages for easy data analysis. 
This database platform has several practical advantages: 
• 
HIPAA Compliant 
• 
Data is stored on a secure server 
• 
Database access requires user authentication with password 
• 
Data access based on an individual’s role on a project 
• 
Logging and audit trails on all data interactions 
• 
IRB and UF Privacy Office approved for collection and storage of PHI (private health 
information). 
The University of Florida (UF) requires that all data collected or stored in REDCap follow the 
following processes and procedures: 
• All human research studies must have Institutional Review Board (IRB) approval before 
the research study can be moved to production and data collection can commence. 
• The name of the Principal Investigator (PI) must be provided. 
• If the research study will include other collaborative personnel such as co-investigators, 
technicians and students, the principal investigator must assure that the personnel are listed 
on the approved IRB form. 
• If data is collected that is considered either sensitive, protected health information, or 
HIPAA information, then prior to using the system the user must complete all necessary 

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training including but not limited to require HIPAA training. 
• Social Security Number training is required annually for all UF personnel who use SSNs 
in their work or research. The “Protecting Social Security Numbers” training module is 
available only through myTraining. http://mytraining.hr.ufl.edu. 
• It is the responsibility of the principal investigator to ensure that collaborative personnel 
have the appropriate study-specific and related training and have reviewed the required 
safeguards according to UF policies and procedures. 
• Users of REDCap™ must adhere to all UF computer policies, regulations, rules and 
standards. It is the responsibility of the principal investigator and the administrator of each 
account to routinely monitor their REDCap projects. 
 
REDCap Support and Contingency Policies 
The Clinical and Translational Science Institute (CTSI) at the University of Florida provides the 
use of REDCap™ (Research Electronic Data Capture) software as a service for UF investigators 
and their teams to collect study data. This service includes the REDCap application software hosted 
in a web server, server space for data storage, regular system backups, software patches and 
upgrades. In the event of a system shut-down, a 24 hour recovery time objective is achievable. UF 
Health IT has a Disaster Avoidance and Recovery Plan that covers responsibilities, 
communication, and escalation. The recovery point objective for the REDCap database is 1 hour 
(no more than 1 hour of data loss). The recovery point objective for the web server is 24 hours (no 
more than 24 hours of data loss). 
• PIs will maintain printed copies of REDCap forms to enable offline data collection and 
subsequent data entry if there is a need to collect data during an outage. In the event of an expected 
catastrophic disaster, such as loss of a data center due to a hurricane, the REDCap Support Team 
(Administrators) will notify all REDCap users via e-mail of the potential threat. 
• PI’s are advised to move/export data to a disk and to a storage area approved for sensitive data. 
In the event of scheduled System maintenance, the REDCap Support Team (Administrators) will 
notify all REDCap users via e-mail one week prior, one day before and on the day of the scheduled 
maintenance. All users are notified via e-mail when the system is available again. Data is not 
available for export from REDCap during a REDCap outage. 
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 Principal Investigator 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 Principal Investigator (and its representatives), 
relevant regulatory authorities and ethical committees may require access to their full medical 
records for monitoring and auditing purposes. 
Database and results of statistical analyses, narratives of SAEs will be transmitted to Inventiva SA 
which will contract out study report writing. 
The clinical study report will be reviewed and signed by the Principal Investigator. 
The study (validation of the final report), the data will be totally anonymized and will be stored on 
a dedicated and secured slot at the Principal Investigator site. 
Only authorized Principal Investigator employees or its representative will have access to the data. 
 
 

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7.3 
Data Management 
7.3.1 
Responsibilities 
The PI will designate the Data Managers who will be provided with all tools, instructions, and 
training necessary to complete the eCRF into REDCap, and each user will be issued a unique 
username and password. 
The Data Management will be responsible for data processing, in accordance with REDCap data 
management procedures. Data will be managed by the PI (Dr. Cusi) and his research team, who 
will be responsible for data processing, quality control, storage, monitoring, and analysis. Data 
will be also shared with Inventiva for additional analysis and result publication. Only de-identified 
datasets from which all PHI has been removed will be shared with Inventiva. 
The Principal Investigator, together with his designated medical staff, will 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 will not enter data in the eCRFs. 
 
7.3.2 
Data Collection and Validation 
All clinical, laboratory and imaging data will be entered into the eCRF at the investigational site. 
This will be done for each patient (screen failure and enrolled), by the Investigator or designee, 
and signed by the Investigator. A hard copy of the clinical data will be kept in locked cabinets and 
locked offices at our CTSI (second floor, diabetes research section), strictly following current UF 
IRB privacy guidelines of confidentiality at all times. 
A unique subject code will identify the subjects on the eCRF. Each participant will be assigned a 
unique study identification number. A link to the study identification number will be stored 
separately. Data will be collected on case report forms or source documents. Data quality control 
will be monitored regularly along with real-time programmed data checks. 
Once clinical data of the eCRF have been entered into REDCap, 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 in REDCap will be determined in advance 
and documented on the “delegation form”. 
Automatic checks and listings will be designed and performed according to the data validation 
plan, developed by Data Managers. 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. 
 
7.3.3 
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. 

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The medical coding will be performed by the Data Manager coding specialist and reviewed by a 
Principal Investigator before being submitted to Inventiva for approval. 
 
7.3.4 
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. 
 
7.3.5 
Database Transfer 
Final validated data will be transferred in a secure way to the Inventiva Biostatistical team in Excel 
or the format that best meets the Inventiva Biostatistical team after mutual agreement. 
 
7.4 
Independent Audit 
The Principal Investigator will permit an independent audit by an auditor mandated by Inventiva 
S.A., 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. 
 
7.5 
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, 
Inventiva S.A. will be informed without delay. 
 
 
8 
Statistical Methods 
Studied population: 
Modified ITT and safety population: All randomized patients who took at least one dose 
Evaluable patients: Patients belonging to the mITT with at least one pre-randomization and one 
post-randomization assessment of IHTG. 
 
8.1 
Efficacy Assessments 
Primary outcome and Primary efficacy criterion: IHTG quantified by ¹H-MRS. 
Primary outcome: Change from baseline to week 24 in IHTG quantified by 1H-MRS. 
Primary measure of the magnitude of treatment effect: difference between lanifibranor and 
placebo in the mean change from baseline to week 24 of IHTG. 
Threshold of clinical pertinence of the effect size: an absolute difference between treatments of 
3% in the mean change from baseline to week 24 is probably at the limit of clinical pertinence. 
This represents a mean decrease in IHTG of 20% in lanifibranor group and 0% in placebo group. 
Considering a standard deviation of 7 this is a standardized effect size of a little less than 0.43 
which is in the lower-medium class (between 0.4 and 0.5) of treatment effect. Therefore, an 
absolute reduction of 3.5% (relative reduction of 23.3%), leading to a standardized effect size of 
1.5 (medium effect size), is considered clinically pertinent. Indeed, assuming the normality of the 
distribution of the change from baseline, a mean absolute reduction of 3.5% in IHTG for the tested 
drug and 0 for placebo, a baseline at 15%, a standard deviation of 7% and a resolution of NAFLD 

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from 5.5% and below, the expected percentage of patients with A IHTG of 5.5 or less ("resolution" 
of NAFLD) is 19.5% with the tested drug and 8.7% for the placebo corresponding to a 2.24 times 
more chance of observing a resolution in the tested drug than in the placebo group. 
Using the expected treatment effect in the sample size calculation (35% relative reduction in IHTG 
for the tested drug and 0% for placebo), then the expected absolute effect size is 5.5%, the 
standardized effect size is 0.79 that is very close to a large magnitude (0.8) of treatment effect. The 
expected percentages of "resolution" of NAFLD under the assumption of normality of the change 
from baseline is 28.4% versus 8.7% corresponding to 3.26 times more chance to get an observed 
resolution of NAFLD for lanifibranor compared to placebo. 
Secondary endpoints: The following changes from baseline to 24 weeks of treatment will be 
evaluated and used as secondary endpoint: 
• Proportion of “responders” defined as the percentage of patients reaching a decrease 
from baseline in IHTG (quantified by ¹H-MRS) of ≥ 30% at 24 weeks. The definition 
of “responders” as those with a ≥ 30% reduction in liver fat by ¹H-MRS is empiric as 
there are no studies (except the Belfort et al, NEJM 2006 (1) and Cusi et al (2) with 
pioglitazone) comparing simultaneously ¹H-MRS with liver histology, but this threshold 
is likely to correlate with positive histological changes in NASH, based on investigator's 
experience. 
• Proportion of patients considered as having resolution of NAFLD (≤5.5% IHTG 
quantified by 1H- MRS) at 24 weeks (highly likely to translate into histological benefit 
in NASH). 
• Changes in hepatic fibrosis by several techniques (one or all may be used): 
a) vibration-controlled transient elastography (Fibroscan) (3); 
b) two-dimensional magnetic resonance elastography (2D-MRE) (4); and 
c) T1  MRI  mapping  scanning  protocol  that  allows  for  the  accurate  non-invasive 
measurement of liver fibrosis (5). 
• Change in plasma biomarkers of liver fibrosis (i.e., cytokeratin CK-18, proC3. 
• Change in metabolic outcomes standard for such pilot trials (see our work in ref. 1,2,6 
at week 24 of treatment, and will include: 
o Determination 
of glucose 
tolerance/insulin, 
hepatic 
insulin 
sensitivity, 
gluconeogenesis, de novo lipogenesis (DNL). 
o Oral glucose tolerance test. 
o Glycemic control: HbA1c, advanced lipid testing. 
o Biomarkers  of  adipose  tissue  metabolism  (i.e.,  plasma  adiponectin  and 
adipokine panels measured multiplex platform). 
• DNA testing to assess SNPs related to NAFLD (PNPLA3, TM6SF2, others) (36). 
• Safety and tolerability assessments as standard for clinical treatment trials (vital signs, 
electrocardiograms, hypoglycemia, laboratory parameters such as elevation in liver or 
pancreatic enzymes, other). 
 
8.2 
Sample Size 
Based on the most recent studies patients with NAFLD are expected to have a baseline IHTG of 
approximately 15%. The earlier power calculations based on results with pioglitazone from a 6- 
month study (1) and a more recent 18 month RCT (2) but they were revised in the  protocol based 
on the recent results with lanifibranor 800 mg/day (same dose as this study), a 6-month RCT 
(NATIVE) that used liver biopsy (histology) as the primary endpoint (provided in detail by 
Inventiva to the PI Dr. Cusi). In NATIVE, the proportion of patients with a reduction in steatosis 

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to lanifibranor was 73% versus 26% with placebo; greater than with pioglitazone in the 6-month 
Belfort et al study [1]). Based on these most recent results, this would translate to liver fat imaging 
on 1H-MRS of a relative reduction of fat liver with lanifibranor to be ≥50% compared to placebo. 
This represents a change of ≥7.0% with lanifibranor versus the control group. The expected 
standard deviation of the change from baseline is expected to be 7%. Considering a type I error of 
0.05 (2-sided), a power of 0.80, an allocation ratio of 1:1, the same variance in both treatment 
groups and a parametric test of mean comparison, the required sample size per group is 15 patients 
to complete treatment. Assuming that 10 % of randomized patients will not complete the trial, the 
total number of patients to be randomized is 33-34 patients. Considering a type I error of 0.05 (2-
sided), a power of 0.80, an allocation ratio of 1:1, the same variance in both treatment groups and 
a parametric test of mean comparison the required sample size per group is 15 patients. Assuming 
that 10 % of randomized patients will not complete the trial, the total number of patients to be 
randomized is 34. 
 
8.3 
Randomization 
Patients will be randomized equally 1:1: to either dose of lanifibranor or placebo. 
The randomization list will be setup with blocs of size equal to 4. 
8.4 
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. 
 
8.5 
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. This set is the primary 
set of patients used in the primary analysis of the primary efficacy endpoint. It corresponds more 
or less to efficiency evaluation of treatment. 
 
- 
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. In case 
of no post-randomization efficacy assessment the patient will be a failure (see handling of missing 
data). This set of patients will be used in a sensitivity analysis. 
 
- 
Set of evaluable patients 
The set of evaluable patients will consist of the FAS after exclusion of all patients who did not 
have an efficacy evaluation (IHTG) at week 24. Patients did not necessarily took their treatment 
up to week 24. 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. 
 
- 
Per protocol set of completers 
This set is composed of all patients who completed the treatment and the study and who were free 
from major protocol deviation that can bias the estimation of the treatment effect at week 24. 
Patients with major deviations will be listed during the blind review and the reason for exclusion 
will be provided. In case of treatment error, the patient will be assigned to the group corresponding 
to the actual treatment received. This set will be used in efficacy evaluation for estimating and 
testing the treatment effect in the best situation (squeaky clean analysis) i.e. treatment completers, 

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assessment at 24 weeks for all patients, no major protocol violations 
 
- 
Safety set of patients 
The safety set of patients will include all patients who have taken at least one dose of treatment 
(IVA 337 or placebo), regardless any protocol deviations. In case of treatment error, the actual 
treatment will be used. Safety analyses will be conducted on the safety population 
 
 
8.6 
Demographic and Other Baseline Characteristics 
8.6.1 
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, median minimum and 
maximum for quantitative values and counts and percentages for qualitative variables). 
 
8.6.2 
Previous Medications 
The use of prior medications will be summarized. 
 
8.6.3 Patient history 
Medical history of patients will be provided 
 
8.7 
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 Principal Investigator will use 
its most updated list of potentially clinically significant abnormalities (PCSA) in clinical laboratory 
tests, vital signs, and ECG for the final analysis. The effect of the demographic differences (gender, 
age, etc.) and risk factors of clinical relevance will be explored in case of any potential concern. 
 
8.7.1 
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). In case of treatment 
interruption, the actual duration of treatment will be used. The distribution and cumulative 
distribution of patients by treatment exposure duration will be presented graphically for the safety 
population. 
 
8.7.2 
Adverse Events 
Each AE will be associated to a "preferred term" and classified by "system-organ class" according 
to the latest MedDRA. The AE parameter of interest is the number and percentage of patients 
experiencing: - at least one event - an event under each recorded preferred term, and an event under 
each recorded system-organ class. These frequencies 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 

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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 same manner as TEAEs. 
- 
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 allocated treatment.  Summary 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 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. 
 
8.7.3 
Other Observations Related to Safety 
- 
Laboratory tests 
The analysis will focus on potentially clinically significant abnormal (PCSA) values which will be 
defined in the Statistic Analysis Plan (SAP). The incidence of PCSAs will be summarized for each 
clinical laboratory test. The summaries 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 as well as the PCSA values. 
 
- 
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 
values for all visits will be provided. Patients with PCSA for each vital sign or ECG data parameter 

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will be identified and listed. The incidence of PCSA at any time point will be summarized for each 
vital sign parameter. The summaries will include patients who have at least one measurement 
performed after the first study product intake. When the PCSA definition involves a change from 
the baseline value, patients also need to have a baseline value to be included in the summaries. 
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 as well as the PCSA values. 
 
- 
Physical examination 
For physical examination anomalies will be listed and frequencies tables will be computed. 
 
8.7.4 
Efficacy Analyses 
Primary efficacy analysis 
The primary population will be the modified intent to treat FAS population composed of all 
randomized subject who received at least one dose and had at least one post-randomization efficacy 
assessment. 
The primary outcome will be the change from baseline to week 24 in IHTG. 
The primary model will be a general linear model using the change from baseline to week 24 as 
the response, the treatment as covariate as well as the baseline of IHTG. Few covariates can be 
added in the SAP to take into account known confounding factors. 
The magnitude of the treatment effect will be the between treatment group difference in the mean 
change from baseline to week 24 in IHTG adjusted for baseline of IHTG. 
The primary rule for handling the IHTG missing data at Week 24 is the use of the baseline at Week 
24 in case the mean change from baseline in placebo group is equal to zero or is an improvement 
or if the reason for missing data is definitely not related to treatment or disease progression. If the 
relative change from baseline to week 24 in the placebo group is a deterioration of IHTG then the 
relative deterioration observed in the placebo group will be applied to all missing IHTG at week 
24 that are possibly related to treatment or disease progression. 
 
Sensitivity analyses 
The primary analysis of the primary efficacy assessment will be performed after the following 
modification. 
• Use of the randomized set of patients. 
• Use of the evaluable set of patients 
• Use of the per protocol set of patients 

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• Use of a non-parametric test (Mann and Whitney) especially in case of outliers or if the 
distribution of change from baseline is quite skewed. Hodge Lehmann estimator will be 
used to estimate the magnitude of treatment effect. 
• Use of the Q3 (third quartile) estimate of the relative change from baseline to week 24 of 
the placebo distribution (from the most improved to the most worsened) for imputing 
missing IHTG at week 24. 
 
Secondary efficacy analyses of the primary efficacy assessment 
The following proportions will be estimated per treatment group with the Clopper Pearson 95% 
CI and compared with a Fisher exact test in the FAS, the evaluable set of patients and per protocol 
set of patients: 
• Proportion of “responders” defined as the percentage of patients reaching a decrease 
from baseline in IHTG (quantified by 1H-MRS) ≥ 30% at 24 weeks. In case of missing 
outcome at weeks 24 the patient is a non-responder. 
• Proportion of patients considered as having resolution of NAFLD (≤ 5.5% IHTG 
quantified by 1H- MRS) at 24 weeks. 
 
Other secondary analyses 
• Between treatment difference in the change from baseline to week 24 in hepatic fibrosis 
will be estimated and tested with a general linear model for each technique used: 
a) Vibration-controlled transient elastography (Fibroscan); 
b) two-dimensional magnetic resonance elastography (2D-MRE); and 
c) T1 MRI mapping. 
The general statistical approach will be similar to the primary analysis and subordinated 
analyses. 
 
• Between treatment difference in the change from baseline to week 24 in each plasma 
biomarkers of liver fibrosis (cytokeratin CK-18, proC3) will be estimated and tested 
using the same approach as the primary analysis. 
 
• Between treatment difference in the change from baseline to week 24 in metabolic 
outcomes will also be estimated and tested for: 
o Hepatic insulin sensitivity, gluconeogenesis and de novo lipogenesis (DNL). 
o Oral glucose tolerance test. 
o Glycemic control: HbA1c, advanced lipid testing. 
o Biomarkers  of  adipose  tissue  metabolism  (i.e.,  plasma  adiponectin  and 
adipokine panels measured by the gold-standard Millipore multiplex platform). 
• The percentage of patients achieving an improvement in HbA1c or plasma lipid targets 
will be analyzed using a logistic regression model with treatment and baseline HbA1c 
and lipid profile as covariates, respectively. 
• The time course of repeated measures of FPG, HbA1c, lipid parameters, and others will 
be estimated and tested using mixed models for repeated measures to account for the 
correlation amongst measures after careful selection of the proper covariance structure. 
• Hypoglycaemia rate will be fitted to a negative binomial model to test the treatment 
effect. 
• The percentage of patients having a hypoglycaemia reported or not as AE will be 

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analyzed using a loglikelihood test, unless there are too few events in which case a 
Fisher exact test will be used. 
• DNA testing to assess SNPs related to NAFLD (PNPLA3, TM6SF2, others). 
• Immunohistochemistry: 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 
Wilcoxon Mann Whitney test. 
Planned exploratory analyses: 
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. 
 
 
9 
Patient Withdrawal & Replacement 
& Clinical Trial 
Stopping Rules 
9.1 
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 
• 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 section 
4.3.3) 
• Any deterioration in cardiac status 
• CTCAE grade 3 or higher possibly or probably related to study drug OR CTCAE grade 4 
or higher regardless of attribution to study drug 
• Additional individual discontinuation should be based on known toxicities and side effects 
of the drug and its class, specifically for metabolic, renal, hematologic, and hepatic toxicity. 
If any of the following criteria are met, the patient should be immediately discontinued 
from drug and followed until resolution of adverse events and laboratory values have 

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returned to baseline. 
1. Total Bilirubin ≥ 3.0 md/DL 
2. Total CPK > 5X ULN 
3. Lipase level increase above inclusion criteria (i.e., lipase above 1.3X ULN if not on a 
DPP-IV inhibitor, or >2.0X ULN if on a DPP-IV inhibitor) and re-confirmed on testing 
within 7 days; or lipase > ULN in any patient with symptoms compatible with 
pancreatitis; or in asymptomatic patient with lipase above inclusion criteria and when 
retested (without drug interruption) remains above inclusion criteria within 7 days. 
4. eGFR with a decrease of more than 20% below the lower limit of inclusion criteria (or < 
48 ml/min/1.73 m2) and where the value is reconfirmed after 24 - 48 hours repeat. 
Additionally, any subject who requires renal replacement therapy should also be 
discontinued from drug. 
5. Hemoglobin < 10 mg/dL or HCT < 30% 
6. Platelets < 100,000 per microliter of blood 
7.   WBC < 2.5 x 109/L and /or ANC <1.5 K/µL 
8. Regarding hepatic toxicity 
o For BLM < 2x ULN, for ALT or AST >5x BLM 
o For BLM ≥2X ULN but < 5X ULN, for ALT or AST > 3X BLM 
o For BLM ≥ 5X ULN, for ALT or AST > 2X BLM 
o For ALT or AST increase > 2X BLM accompanied by a concomitant total 
bilirubin increase to > 2X BLM OR an INR increase by > 0.2 
For elevations of liver enzymes accompanied by symptoms consistent with 
hepatic injury [e.g., fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia 
(>5%)]http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
• 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 section 6.2.2), the patient will be followed until 
outcome, i.e. at least on a quarterly basis for follow-up evaluation of the pregnancy, fetus, 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 
analyzed at the end of the study, and the biological samples stored up to one year after the 
completion of the study and destroyed. 
 
9.2 
Study Stopping Rules 
In addition, the trial will be stopped if: 

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1. Three patients develop the same Grade 3 CTCAE 
2. OR two patients develop any Grade 4 CTCAE  
3.  OR one patient develops a Grade 5 CTCAE 
9.3 
Unblinding Process 
9.3.1 
Unblinding for emergency 
The code breaks sealed envelopes will be provided and will be kept by the Principal Investigator. 
The Principal Investigator is responsible for ensuring appropriately trained staff members are 
available to open code breaks sealed envelopes 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 section 2.3). 
Details of any emergency unblinding shall be documented fully in the Investigator’s file and 
research pharmacy file(s). This includes, but may not be limited to: 
1) Date, 
2) Subject details, 
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 trial research pharmacy or an individual as named on the Delegation Log has 
performed the procedure, they will inform the Principal Investigator, 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. 
 
 
9.3.2 
Unblinding for DSMB 
The Principal Investigator will create a University of Florida Data Safety and Monitoring Board 
(DSMB) to ensure safety surveillance during the study. This safety committee may recommend 
unblinding of any data for further analysis is deemed necessary for the safety of the subjects. If so, 
the Principal Investigator will be notified, and an independent ad hoc group will be created in order 
to maintain the blinding of the study and of the participating personnel. 
 
 
9.3.3 
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. 
 
 
10 
Training & Information 
10.1 
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. 

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10.2 
Information of the Investigator 
The investigator will receive all the relevant information for a safe use of the IMP as the study 
proceeds. 
 
 
11 
Records & Data 
11.1 
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. 
 
 
11.2 
Case Report Forms 
Electronic Case Report Form (eCRF) will be provided by the research team. 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. 
 
 
12 
Confidentiality 
12.1 
Confidentiality of Patient Data 
The Principal investigator will ensure that the confidentiality of the patients’ data is preserved. On 
eCRFs or any other documents for the patients will not be identified by their names, but by a study 
code. Documents not for transmission e.g. the confidential PHI and the signed informed consent 
forms will be maintained by the investigator in strict confidence. 
These data will be collected and processed with full precautions to ensure confidentiality and 
compliance with applicable UF IRB data privacy protection laws and regulations. Technical and 
organizational measures will be in place to fully protect PHI against unauthorized disclosures or 

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access, accidental or unlawful destruction, or accidental loss or alterations. Any personnel with 
access to personal data must agree to keep the identity of subjects strictly confidential. 
The informed consent that will be obtained from all participants includes explicit consent to access 
and process PHI and for the investigator/institution to allow direct access to the original medical 
records (source data/documents) for study-related monitoring, audit, IRB review, and regulatory 
inspection. This consent also addresses the transfer of de-identified datasets to be shared with to 
other countries (e.g., Inventiva headquarters) or other authorized entities (e.g., FDA). 
The participant retains the right to request through the PI access to their personal data and 
rectification of any data considered to be incorrect or incomplete. Reasonable steps will be taken 
to respond to these requests, taking into consideration the nature of the request, the conditions of 
the study, and the applicable laws and regulations. 
 
12.2 
Confidentiality of 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 Inventiva S.A. Any data, results, 
inventions and patents that may arise from this study will be the exclusive property of Inventiva 
S.A. 
 
 
13 
Reporting & Publication 
13.1 
Study Report 
All the relevant data and information will be reported in a study report prepared by a CRO and 
submitted to the investigators for review comments and signature. The final study report will be 
used for the further development of the IMP and regulatory submissions. 
 
 
13.2 
Disclosure of Data and Publications 
No information provided by Inventiva SA 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 
SA. 
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 Principal Investigator 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 SA 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 SA 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 SA with complete test results and all data derived from the 
study in accordance with the protocol. 
Only Inventiva SA and its authorized contractor may make information obtained during the study 
available to regulatory agencies, except as required by regulation. 
 

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14 
Record Keeping 
14.1 
Study Site Records 
The Principal 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 Principal 
Investigator will complete the confidential patient identification list which provides the sole link 
between source records and anonymous eCRF data. The Principal 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 Principal Investigator and Inventiva S.A. If the Principal Investigator 
intends to assign the study documents to another party, or to move them to another location, 
Inventiva S.A. must be notified. 
 
 
14.2 
Study Master File 
The Principal Investigator will archive the study master file in accordance with GCP and applicable 
regulatory requirements. 
 
 
15 
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hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in 
steatohepatitis. Cell Metab. 2015;21(5):739–46. 
33. Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle 
and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 
2011;14(6):804–10. 
34. Beysen C, Murphy EJ, Nagaraja H, Decaris M, Riiff T, Fong A, et al. A pilot study of the 
effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes. J Lipid 
Res. 2008;49(12):2657–63. 
35. American Diabetes Association. Diabetes Care 2018;41(S1): S55-S64. 
36. Yki-Järvinen H. Diagnosis of non-alcoholic fatty liver disease (NAFLD). Diabetologia. 2016 
Jun;59(6):1104–11. 

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16 
APPENDICES 
16.1 
Appendix A: World Medical Association Declaration of Helsinki 
 

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16.2 
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). To be measured at all visits. 
 
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. To be done at all visits. 
 
3. ELECTROCARDIOGRAM RECORDINGS 
A 12-lead standard ECG to be performed at V1 (screen) and at V11 (24 weeks). 
 
 

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16.3 
Appendix C: Procedure for Preparation of (6,6-D2)-Glucose Infusates 
 
Preparation of 2D-glucose infusates 
 
Date: 
Subject: 
Operator: 
 
 
(6,6-2D)-glucose 
(0.50 gm/ml) 
 
Catalog No.: 
Lot No. 
Date prepared: 
 
 
0.9% NaCl 
 
Catalog No.: 
Lot No.: 
 
 
D20 glucose 
 
Catalog No.: 
Lot No.: 
 
 
 
NOTE: If there are changes in this process during the course of the clinical study, written 
notification will be provided to the Sponsor and the Investigator, and a protocol amendment will 
not be required. The most current version of Standard Operating Procedure for this process is 
maintained at the investigator site. 

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I. Baseline infusion 
 
Materials: 
0.9% NaCl for infusion 
Sterile (6,6-D2)-glucose stock (500 mg/mL) 
 
 
 
Procedure:  
1. Remove overfill (20 ml) of NaCl so that final volume is 250 mL. Use 
sterile needle and syringe. 
2. Add 5.0 ml of sterile 2D-glucose stock. Mix. 
3. Record lot number of NaCl 
 
 
 
II. 20% dextrose infusion:  
1. Add 4.0 mL of sterile 2D-glucose stock to 500 ml bottle of 
D20. Mix. 
2. Record lot number of D20. 
 
 
 
III. (6,6-2D)-glucose stock:  
1. Record catalog and lot numbers of 2D-glucose 
2. Weigh out 2D-glucose – 150 gm 
3. Dissolve in sterile 0.9% NaCl (~200 ml); warm to 37° C if 
necessary. 
4. Adjust final volume to 300 ml with 0.9% NaCl 
5. Sterile filter (0.22 µm). 
6. Aliquot into sterile tubes: 5 mL/tube. 
7. Store aliquots at -5° to 5° C. 
8. Test stock for pyrogenicity and sterility 
 
 
 
Notes: 
All steps but for III.2. are performed in a certified Biosafety cabinet under sterile 
conditions.