Phase 2b Study in NASH to Assess IVA337
Condition: Non-Alcoholic Steatohepatitis (NASH)
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: IVA337; IVA337; Placebo
Intervention description: 1200mg; 800mg; Placebo to match
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 247.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non-Alcoholic Steatohepatitis; NASH; peroxisome proliferator-activated receptor (PPAR); Liver Diseases; Fibrosis; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases; IVA337

Summary:

      Non-alcoholic steatohepatitis, abbreviated as NASH, is a chronic liver disease that may
      progress to cirrhosis. The disease is mostly associated with obesity and type 2 diabetes
      mellitus, or insulin resistance and is very common. However, Treatment of NASH is a
      significant unmet clinical need.

      IVA337 (lanifibranor) is a next generation pan-PPAR (peroxisome proliferator-activated
      receptors) agonist addressing the pathophysiology of NASH : metabolic, inflammatory and
      fibrotic.

      The purpose of this research is to evaluate the efficacy and the safety of two doses of
      IVA337 (800mg, 1200 mg) per day for 24 weeks versus placebo in adult NASH patients with liver
      steatosis and moderate to severe necroinflammation without cirrhosis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adult subjects, age ≥18 years.

          -  NASH histological diagnosis according to the currently accepted definition of both
             EASL and AASLD, requiring the combined presence of steatosis (any degree ≥ 5%) +
             lobular inflammation of any degree + liver cell ballooning of any amount, on a liver
             biopsy performed ≤ 6 months before screening in the study or at screening and
             confirmed by central reading during the screening period and

               -  SAF Activity score of 3 or 4 (>2)

               -  SAF Steatosis score ≥ 1

               -  SAF Fibrosis score < 4

          -  Subject agrees to have a liver biopsy performed after 24 weeks of treatment.

          -  Compensated liver disease

          -  No other causes of chronic liver disease (autoimmune, primary biliary cholangitis,
             Hepatitis B virus (HBV), hepatitis C virus (HCV), Wilson's, α-1-antitrypsin
             deficiency, hemochromatosis, etc…).

          -  If applicable, have a stable type 2 diabetes, defined as HbA1c ≤ 8.5% and fasting
             glycemia <10 mmol/L, no changes in medication in the previous 6 months, and no new
             symptoms associated with decompensated diabetes in the previous 3 months.

          -  Have a stable weight since the liver biopsy was performed defined by no more than a 5
             % loss of initial body weight.

          -  Negative pregnancy test or post-menopausal. Women with childbearing potential (i.e.
             fertile, following menarche and until becoming post-menopausal unless permanently
             sterile) must be using a highly effective method of contraception (i.e. combined
             (estrogen and progestogen containing) hormonal/ progestogen-only hormonal
             contraception associated with inhibition of ovulation, intrauterine device,
             intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised
             partner). The contraceptive method will have to be followed for at least one
             menstruation cycle after the end of the study

          -  Subjects having given her/his written informed consent.

        Exclusion Criteria:

          -  Evidence of another form of liver disease.

          -  History of sustained excess alcohol ingestion: daily alcohol consumption > 30 g/day (3
             drinks per day) for males and > 20 g/day (2 drinks per day) for females.

          -  Unstable metabolic condition: Weight change > 5kg in the last three months, diabetes
             with poor glycemic control (HbA1c > 8.5%), introduction of an antidiabetic or of an
             anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the
             past 6 months prior to screening.

          -  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.

          -  Significant systemic or major illnesses other than liver disease, including congestive
             heart failure (class C and D of the American Heart Association , AHA), unstable
             coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure,
             organ transplantation, serious psychiatric disease, malignancy that, in the opinion of
             the investigator, would preclude treatment with IVA337 and/or adequate follow up.

          -  HB antigen >0, HCV Polymerase chain reaction (PCR) tests >0 (patients with a history
             of HCV infection can be included if HCV PCR is negative since more than 3 years), HIV
             infection.

          -  Pregnancy/lactation or inability to adhere to adequate contraception in women of
             child-bearing potential.

          -  Active malignancy except cutaneous basocellular carcinoma.

          -  Any other condition which, in the opinion of the investigator would impede competence
             or compliance or possibly hinder completion of the study.

          -  Body mass index (BMI) >45 kg/m2.

          -  Type 1 diabetes and type 2 diabetic patient on insulin.

          -  Diabetic ketoacidosis

          -  Fasting Triglycerides > 300 mg/dL.

          -  Hemostasis disorders or current treatment with anticoagulants.

          -  Contra-indication to liver biopsy.

          -  History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease
             event, including myocardial infarction, except patients with only well controlled
             hypertension. Any clinically significant ECG abnormality reported by central ECG
             reading.

          -  Participation in any other clinical study within the previous 3 months.

          -  Have a known hypersensitivity to any of the ingredients or excipients of the
             Investigational medicinal product (IMP)

          -  Be possibly dependent on the Investigator or the sponsor (e.g., including, but not
             limited to, affiliated employee).

          -  Creatine phosphokinase (CPK)>5 x ULN

          -  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.

        (The criteria below are applicable only for patients who will undergo a MRI/LMS in selected
        centers)

          -  Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation
             is permitted at discretion of investigator.

          -  Metallic implant of any sort that prevents MRI examination including, but not limited
             to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural
             stimulator, metallic contraceptive device, tattoo, body piercing that cannot be
             removed, cochlear implant; or any other contraindication to MRI examination.