Phase 2b Study in NASH to Assess IVA337

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

Detailed Description
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Randomized (stratified on diabetes), placebo-controlled, double-blind, parallel-assignment, dose-range multicenter study There are 3 parallel treatment groups: placebo, IVA337 800mg once a day (Quaque Die, QD) and IVA337 1200mg QD (identical tablets of 400mg IVA337 or placebo). Both, patient and investigator are blinded. For each patient, the study duration will be an overall of 6 to 8 months (with a 10-day to 4-week selection period, a 24-week treatment period and a 4-week follow-up period).

Official Title
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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)

Conditions
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Non-Alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: IVA337
* Drug: IVA337
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IVA337 1200mg<br>IVA337 400mg, once a day (Quaque Die, QD) with food | Drug: IVA337<br>* 1200mg<br>|
| Experimental: IVA337 800mg<br>IVA337 400mg, once a day (Quaque Die, QD) with food | Drug: IVA337<br>* 800mg<br>|
| Placebo Comparator: Placebo<br>Placebo to match, once a day (Quaque Die, QD) with food | Drug: Placebo<br>* Placebo to match<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F) | SAF-A is the activity part of the Steatosis Activity Fibrosis [SAF] histological score, calculated as the sum of lobular inflamation score and balloning score. No worsening of fibrosis means that the CRN fibrosis score (CRN-F) remains stable or decreases. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NASH Improvement | NASH improvement is defined as a decrease of at least 2 points in NAS score (sum of CRN Steatosis, Inflammation and Ballooning scores) without worsening of CRN Fibrosis score. | 24 weeks | 
| NASH Resolution and no Worsening of Fibrosis | Resolution of NASH is defined as a CRN Inflammation score equal to 0 or 1, and a CRN Ballooning score equal to 0. No worsening of fibrosis means that the CRN fibrosis score remains stable or decreases. | 24 weeks | 
| Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH | Improvement of fibrosis is defined as a decrease of at least one stage in CRN Fibrosis score. No worsening of NASH is defined as no increase of CRN Steatosis score, no increase of CRN Inflammation score ans no increase of CRN Ballooning score. | 24 weeks | 
| Activity (SAF-A) Improvement | SAF-A is the activity part of the Steatosis Activity Fibrosis [SAF] histological score, calculated as the sum of lobular inflamation score and balloning score. Improvement of SAF-A is defined as a decrease of at least 1 point. | 24 weeks | 
| Steatosis (CRN-S) Improvement | Improvement of CRN Steatosis score (CRN-S) is defined as a decrease of at least 1 point. | 24 weeks | 
| Lobular Inflammation (CRN-I) Improvement | Improvement of CRN Lobular inflammation score (CRN-I) is defined as a decrease of at least 1 point. | 24 weeks | 
| Hepatocyte Balooning (CRN-B) Improvement | Improvement of CRN Ballooning (CRN-B) is defined as a decrease of at least 1 point. | 24 weeks | 
| Fibrosis (CRN-F) Improvement | Improvement of CRN Fibrosis score (CRN-F) is defined as a decrease of at least 1 point. | 24 weeks | 
| Modified ISHAK Fibrosis (ISHAK-F) Improvement | Improvement of Modified ISHAK Fibrosis (ISHAK-F) is defined as a decrease of at least 1 point. | 24 weeks | 
| Absolute Change in ALT | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change in AST | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change in GGT | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change in Fibrinogen | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change in Hs-CRP | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change in Alpha2 Macroglobulin | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change in Haptoglobulin | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. | 24 weeks | 
| Absolute Change of Fasting Plasma Glucose | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in Insulin | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in HOMA Index | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in HbA1c | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in Total Cholesterol | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change of HDL-Cholesterol | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change of LDL-Cholesterol | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in Triglycerides | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in Apo A1 | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Absolute Change in Adiponectin | Absolute change is defined as Week 24 value - baseline value. Baseline value was defined as the last available non-missing data before or equal to the treatment start. Only fasting values were considered. | 24 weeks | 
| Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage | Resolution of NASH is defined as a CRN Inflammation score equel to 0 or 1, and a CRN ballooning score equal to 0. Improvement of firbosis is defined as a decrease of at least one stage in CRN Fibrosis score. | From baseline to Week 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Alcoholic Steatohepatitis, NASH, peroxisome proliferator-activated receptor (PPAR), Liver Diseases, Fibrosis, Fatty Liver, Non-alcoholic Fatty Liver Disease, Digestive System Diseases, IVA337