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
- onalcoholic steatohepatitis (NASH)MedDRA version: 22.0Level: PTClassification code 10053219Term: Non-alcoholic steatohepatitisSystem Organ Class: 10019805 - Hepatobiliary disordersTherapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]
- Registration Number
- EUCTR2016-001979-70-PL
- Lead Sponsor
- Inventiva S.A.S
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 225
-Adult subjects, age =18 years.
-NASH histological diagnosis according to the currently accepted definition of both EASL and AASLD (1–3), requiring the combined presence of steatosis (any degree = 5%) + lobular inflammation of any degree + liver cell ballooning of any amount, on a liver biopsy performed = 6 months before screening in the study or at screening and confirmed by central reading during the screening period and
a.SAF Activity score of 3 or 4 (>2)
b.SAF Steatosis score = 1
c.SAF Fibrosis score: < 4
-Subject agrees to have a liver biopsy performed after 24 weeks of treatment
-Compensated liver disease with the following hematologic and biochemical criteria before randomization::
oALT < 10xULN
oHemoglobin = 110 g/L (11 g/dL) for females and = 120 g/L (12 g/dL) for males
oWhite blood cell (WBC) > 2.5 10^9/L (2.5 10^3/µL)
oNeutrophil count > 1.5 10^9/L (1.5 10^3/µL)
oPlatelets > 100 10^9/L (100 10^3/µL)
oTotal bilirubin < 35µmol/L2.06 mg/dL). Patients with bilirubin = 35µmol/L(2.06 mg/dL) can be included if non-conjugated bilirubin in the setting of a Gilbert syndrome.
oAlbumin > 36 g/L(3.6 g/dL)
oInternational Normalized Ratio INR < 1.4
oSerum creatinin < 115 µmol/L (1.3 mg/dL) (men) or < 97 µmol/L (1.1 mg/dL) (women) or estimated glomerular filtration rate = 60 mL/min/1.73m2
-No other cause of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, HCV, Wilson’s, a-1-antitrypsin deficiency, hemochromatosis etc…)considered to have an impact on the patient's
safety or on the efficacy evaluation.
-If applicable, have a stable type 2 diabetes, defined as HbA1c = 8.5% and fasting glycemia <10 mmol/L(180 mg/dL), no introduction of new medication in the previous 6 months, and no new symptoms associated with decompensated diabetes in the previous 3 months. Minor modifications of anti-diabetic treatments or dosages are allowed if done in a context of stable type 2 diabetes, i.e. HbA1c = 8.5% in the previous 6 months.
-Have a stable weight since the liver biopsy was performed defined by no more than a 5 % loss of initial body weight
- Negative pregnancy test or post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming postmenopausal 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 270
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30
-Evidence of another form of liver disease,considered to have an impact on the patient's safety or on the efficacy evaluation.
-History of sustained excess alcohol ingestion in the year before the pre-study treatment biopsy: daily alcohol consumption > 30 g/day (3 drinks per day) for males and > 20 g/day (2 drinks/day) for females.
-Unstable metabolic condition: Weight change > 5% in the last three months, diabetes with poor glycemic control (HgbA1c > 8.5%), introduction of an antidiabetic or of an anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening.
-History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or ingestion of drugs known to produce hepatic steatosis including oral corticosteroids, (at dose >5mg/day prednisone
equivalent), estrogens (at doses greater than those used for contraception or hormone replacement), tamoxifen, methotrexate, tetracycline or amiodarone in the previous 6 months. Corticosteroids
administered by routes other than oral are allowed. One short (<2 weeks) course of oral corticosteroids, more than 3 months before the pre-study treatment biopsy is also allowed.
-Significant systemic or major illnesses other than liver disease, including congestive heart failure (class C and D of the AHA), unstable coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator, would preclude treatment with lanifibranor and/or adequate follow up.
-HB antigen >0, HCV PCR >0 (patients with a history of HCV infection can be included if HCV PCR is negative since more than 3 years), HIV infection.
-Pregnancy or lactation or inability to adhere to adequate contraception in women of child-bearing potential.
-Active malignancy except cutaneous basocellular carcinoma.
-Any other condition which, in the opinion of the investigator would impede competence or compliance or possibly hinder completion of the study
-Body mass index (BMI) >45 kg/m2.
-Type 1 diabetes and type 2 diabetic patient on insulin.
-Diabetic ketoacidosis
-Fasting Triglycerides > 300 mg/dL(3.39 mmol/L).
-Hemostasis disorders or current treatment with anticoagulants.
-Contra-indication to liver biopsy.
-History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease event, including myocardial infarction, except patients with only well controlled hypertension. Any clinically significant
ECG abnormality reported by central ECG reading, confirmed by the Investigator to be Clinically Significant.
-Participation in any other investigational drug study within the previous 3 months.
-Have a known hypersensitivity to any of the ingredients or excipients of the IMP including: Lactose monohydrate, Hypromellose, Sodium laurilsulfate, Sodium starch glycolate (type A), Magnesium stearate,
Opadry™ II 85F18422
-Be possibly dependent on the Investigator or the sponsor (e.g., including, but not limited to, affiliated employee).
-Creatine phosphokinase (CPK)>5 x ULN
- Patient with history of well documented osteopenia. Patient treated with vitamin D and/or Calcium based supplements for preventive reasons can be included.
(The criteria below are applicable only for patients who will undergo a MRI/LMS in selected centers)
Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation is permitted at discretion of investigator
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To assess the safety and the efficacy on the activity part of the Steatosis Activity Fibrosis histological score (inflammation and ballooning) of a 24-week treatment with two doses of Lanifibranor (800, 1200 mg/24h) in NASH adult patients.;Secondary Objective: Pharmacokinetics.;Primary end point(s): The primary endpoint is a binary outcome (responder / non responder). A responder is defined as a decrease from baseline to week 24 of at least 2 points of the SAF activity score combining hepatocellular inflammatory and ballooning score without fibrosis progression. Responder rates will be compared between the placebo and IMP groups at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetes.;Timepoint(s) of evaluation of this end point: At the end of the treatment period (week 24)
- Secondary Outcome Measures
Name Time Method