A placebo-controlled, proof-of-concept study to evaluate the safety and efficacy of Lanifibranor alone and in combination with the sodium-glucose transport protein 2 (SGLT2) inhibitor EmpaGliflozin in patiEnts with Nonalcoholic steatohepatitis (NASH) and type 2 Diabetes mellitus (T2DM)

1. Able to understand the nature of the study, willing and able to comply with
the study procedures and restrictions, and willing to provide informed consent
obtained before any study-related activities
2. The patient is willing to continue on the study in case of moving or
relocating to a different region/city where there would be no active study site
3. Able to communicate meaningfully with the Investigator and legally competent
to provide written informed consent
4. Male or female, aged >= 18 years at the time of signing informed consent
5. Diagnosis of NASH
a. based on a historical (within 12 months prior to Screening) liver biopsy
with a non alcoholic fatty liver disease activity score (NAS) >= 4 with a score
of one or more in each sub-component (steatosis, hepatocyte ballooning, lobular
inflammation) and no documented cirrhosis in the last 12 months prior to
Screening OR
b. NASH screening:
i. High Risk NASH defined as cT1 >=> 875 ms assessed by LiverMultiScan® OR
ii. NASH defined as cT1 >= 825 ms assessed by LiverMultiScan® and hepatic fat
content >= 10% assessed by MRI-PDFF
6. HbA1c at screening >= 7.0 and <= 10.0%, on diet alone, or on metformin (>=
1,000 mg/day), and/or dipeptidyl peptidase 4 inhibitor (DPP-IVi) therapy. Doses
have no qualitative change for 3 months prior to informed consent. These
medicines will be continued at stable doses during the entire study.
7. Negative pregnancy test at Screening for females of childbearing potential
or at least two-year post-menopausal. Women of childbearing potential (i.e.,
fertile, following menarche and until becoming post-menopausal unless
permanently sterile) have to use a highly effective method of contraception
throughout the study and for one month after treatment discontinuation. Highly
effective contraceptive methods are defined as follows: combined (estrogen and
progestogen containing) hormonal contraception associated with inhibition of
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal
contraception associated with inhibition of ovulation (oral, injectable,
implantable), intrauterine device (IUD), intrauterine hormone-releasing system
(IUS), bilateral tubal occlusion, vasectomized partner (provided he is her sole
sexual partner and he has received medical assessment of the surgical success),
and true sexual abstinence (when this is in line with the preferred and usual
lifestyle of the patient) whereas periodic abstinence (e.g., calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.

Liver-related:
1. Documented causes of chronic liver disease other than NASH (see protocol for
details, see exclusion criteria no 50 for autoimmune diseases)
a. Viral hepatitis, documented with
i. Positive hepatitis B surface antigen (HBsAg)
ii. Positive hepatitis C virus ribonucleic acid (RNA) (tested for in case of
known cured hepatitis C virus [HCV] infection or positive HCV serology at
Screening). Patients with a history of HCV infection can be included if HCV PCR
is negative since more than 3 years.
b. Drug-induced liver disease
c. Autoimmune hepatitis
d. Wilson*s disease
e. Hemochromatosis
f. Primary biliary cholangitis
g. Primary sclerosing cholangitis
h. *1-antitrypsin deficiency
2. Histologically documented liver cirrhosis (fibrosis stage F4), based on a
historical biopsy (within 12 months prior to Screening); or diagnosis of
cirrhosis at Screening based on clinic biochemical and imaging criteria
(FibroScan® value confirmed >= 14 kPa and FIB-4 > 3.25 provided to the site by
the central lab)
3. History or current diagnosis of hepatocellular carcinoma (HCC)
4. History of or planned liver transplant
5. Documented history of human immunodeficiency virus (HIV) infection
6. ALT or AST > 5 × upper limit of normal (ULN) at Screening
7. Abnormal liver function as defined by central laboratory evaluation of any
of the following:
a. Albumin < lower limit of normal range (LLN)
b. International normalized ratio (INR) >= 1.3 (unless patient is on
anticoagulants)
c. Total bilirubin level >= 1.5 mg/dL (25.7 µmol/L) (Patients with a documented
history of Gilbert*s syndrome can be enrolled if direct bilirubin is <= 0.45
mg/dL (7.7µmol/L))
8. Hemoglobin < 110 g/L (11 g/dL) for females and < 120 g/L (12 g/dL) for males
9. White blood cell count (WBC) < LLN. A lower count is acceptable in patients
with benign ethnic neutropenia, if considered to be clinical insignificant by
the investigator.
10. Platelet count < 140,000/µL
11. Alkaline phosphatase (ALP) > 2 × ULN
12. Patient currently receiving any approved treatment for NASH or obesity
13. Current or recent history (< 5 years) of significant alcohol consumption,
which is typically defined as higher than 30 g pure alcohol per day for men and
as higher than 20 g pure alcohol per day for women (please also refer to
Section 13.1). No binge drinking during the last year. Consuming 75 g pure
alcohol (male), or 60 g pure alcohol (female), or more in about 2 hours
14. Administration of drugs known to produce hepatic steatosis in the 6 months
prior to Screening (such as high-dose estrogens, methotrexate, tetracycline, or
amiodarone) (see also Section 13.2)

Diabetes related:
15. Diabetes mellitus other than type 2 (e.g., type 1, endocrinopathy, and
genetic syndromes)
16. Diabetic ketoacidosis at Screening
17. Current treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA),
insulin or sulfonylurea or treatment within the last 3 months prior to Screening
18. Patients on pioglitazone in the last 12 months prior to Screening
19. Patients on any of the following medications unless the patient had no
qualitative change in doses of such agents for the past 3 months before
Screening: metformin, DPP-IVi, thiazide or furosemide diuretics, beta-blockers,
or other chronic medications with known adverse effects on glucose tolerance
levels. Patients may be taking stable doses with no qualitative change of
estrogens or other hormonal replacement therapy if the patient has been on
these agents for the prior 3 months. Patients taking systemic glucocorticoids
will be excluded.

Obesity related:
20. Body mass index (BMI) > 45 kg/m2 at Screening
21. Weight change > 5% in the 3 months prior to Screening
22. Introduction of an anti-obesity drug or restrictive bariatric surgery in
the past 12 months prior to Screening or planned bariatric surgery through Week
24
23. Participation in an organized weight loss program (e.g., Weight Watchers®,
Jenny Craig®) in the past 6 months prior to Screening or planned participation
through Week 24

Cardiovascular related:
24. History of (within 3 months prior to Screening) or current unstable cardiac
dysrhythmias
25. NT-proBNP > 900 pg/mL
26. Unstable heart failure including:
a. New, or worsening symptoms of coronary heart disease within the past 3
months prior to Screening
b. Acute coronary syndrome within the past 6 months prior to Screening
c. Acute myocardial infarction in the past 3 months prior to Screening
d. Heart failure of New York Heart Association class (III-IV) or worsening
congestive heart failure, or coronary artery intervention, within the past 6
months prior to Screening
27. Any other clinically significant cardiovascular event requiring
hospitalization within 6 months before Screening
28. Uncontrolled hypertension at Screening (systolic blood pressure [SBP] > 160
mmHg and/or diastolic blood pressure [DBP] > 100 mmHg (under conditions
described in Section 8.2.3.)
29. Stroke or transient ischemic attack within 6 months prior to Screening

General safety:
30. Significant systemic or major illnesses other than liver disease,
(including but not limited to those listed above) and pulmonary disease, organ
transplantation, serious psychiatric disease, that, in the opinion of the
Investigator, would preclude treatment with lanifibranor and/or empagliflozin
and/or adequate follow-up
31. Any condition which, in the Investigator*s opinion, might jeopardize a
patient*s safety or compliance with the protocol, or warrants exclusion from
the study
32. Cancer: Presence or history of malignancy within 5 years prior to Screening
and/or active neoplasm at Screening. History of cancer is allowed only
following 5 years of documented remission with the exception of resolved
superficial nonmelanoma skin cancer
33. History of bladder disease and/or persistent hematuria within 6 months
prior to Screening (transient hematuria which has been documented to have
resolved within one week is acceptable), or current hematuria unless due to a
urinary tract infection
34. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR)
value < 60 mL/min as determined by Modification of Diet in Renal Disease [MDRD]
35. Total creatine kinase > 1.5 x ULN
36. History of pancreatitis, or confirmed pancreatic lipase > 1.3 x ULN, or >
2.0 x ULN upon repeated test within 3 weeks if on a DPP-IVi
37. Concomitant treatment with PPAR-* agonists (fibrates); if treatment with
PPAR-* agonist is discontinued before the Baseline visit, it should be
anticipated that triglycerides remain < 500 mg/dL during the study
38. Patients on Vitamin E at doses >= 400 IU/day; doses of >= 400 IU/day are
allowed when no qualitative change in dose for 6 months prior to Screening
39. SARS CoV 2 infections requiring hospitalization in the last 3 months or
current SARS CoV 2 infection confirmed by a validated test. (A SARS CoV 2 test
is not required for all patients at Screening visit but will be performed
according to local standard practice). In case of previous asymptomatic or mild
SAR CoV 2 infection, the investigator should verify that abnormal lab tests due
to COVID 19 are back to pre COVID 19 status before patient randomization.
40. Major surgery scheduled during the study
41. Known or suspected hypersensitivity to any of the ingredients of the
investigational medicinal products (IMPs)
42. Rare hereditary problems of galactose intolerance, total lactase deficiency
or glucose-galactose malabsorption
43. Previous exposure to lanifibranor or empagliflozin
44. Osteopenia, or any other documented bone disease. Patient without
documented osteopenia treated with vitamin D and/or calcium-based supplements
for preventive reasons can be included.
45. Claustrophobia to a degree that prevents tolerance of MRI scanning
procedure. Sedation is permitted at discretion of the Investigator.
46. 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
47. Present pregnancy/lactation or inability to adhere to adequate
contraception in women of childbearing potential
48. Treatment with strong inducers or inhibitors of CYP2C8. When administered
chronically, they should be replaced 3 months before Screening visit. If not
administered chronically, they should be stopped at least 7 days before
treatment initiation (See Section 6.7 and Section 13.2). Prior administration
of other drugs (i.e. weight loss treatments, chronically administered
medications) as specified in Section 13.2.
49. Participation in any clinical trial of an approved or non approved
investigational medicinal product/device within 3 months from Screening or five
half-lives of the investigational drug from Screening, whichever is longer.
Participation in non-interventional trials will be allowed with Sponsor
approval.

F. Autoimmune related:
50. Predisposition to autoimmune liver disease, incl.
a. Signs on previous liver biopsy suggestive of autoimmune liver
disease (autoimmune hepatitis, immune cholangitis or overlap syndrome)
b. Family history of autoimmune liver disease in a first degree
relative
c. Autoimmune thyroid disease:
i. Known diagnosis of autoimmune thyroid disease
ii. Thyroid replacement hormone unless documented for reason of primary thyroid
insufficiency (e.g. due to thyroidectomy, radiation therapy, etc.)
iii. Positive autoimmune antibodies associated with abnormal thyroid function
testing (TSH, T4 or free T3) (1) Anti-thyroid peroxidase antibody (TPO)
iv. Anti-TSH receptor antibodies (TRAb)
d. History of or positive testing at screening for: i. Anti-nuclear antibodies
(ANA) at a dilution of 1:320 or greater
* ii. Anti-mitochondrial antibodies (AMA)
* iii. Anti-smooth muscle antibodies (ASMA) at a dilution of 1:320 or greater
* iv. Anti-liver kidney microsomal type 1 antibodies (LKM1)
* v. Anti-liver cytosol type 1 antibody (LC1)