Phase 2b Study in NASH to Assess IVA337

Phase 2

Completed

• Conditions: Non-Alcoholic Steatohepatitis (NASH)
• Interventions: Drug: IVA337; Drug: Placebo

• Registration Number: NCT03008070
• Lead Sponsor: Inventiva Pharma

Brief 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.

Detailed Description

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).

Study Timeline

• Study First Submitted: 2016-12-22
• Study First Submitted QC: 2016-12-28
• Study First Posted: 2017-01-02
• Study Start: 2017-02-07
• Primary Completion: 2020-02-20
• Study Completion: 2020-03-16
• Results First Submitted: 2021-03-16
• Results First Submitted QC: 2021-03-16
• Results First Posted: 2021-04-12
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-18
• Last Update Posted: 2023-07-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 247

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IVA337 800mg	IVA337	IVA337 400mg, once a day (Quaque Die, QD) with food
Placebo	Placebo	Placebo to match, once a day (Quaque Die, QD) with food
IVA337 1200mg	IVA337	IVA337 400mg, once a day (Quaque Die, QD) with food

Primary Outcome Measures

Name	Time	Method
SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F)	24 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Absolute Change in ALT	24 weeks	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.
NASH Improvement	24 weeks	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.
NASH Resolution and no Worsening of Fibrosis	24 weeks	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.
Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH	24 weeks	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.
Activity (SAF-A) Improvement	24 weeks	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.
Steatosis (CRN-S) Improvement	24 weeks	Improvement of CRN Steatosis score (CRN-S) is defined as a decrease of at least 1 point.
Lobular Inflammation (CRN-I) Improvement	24 weeks	Improvement of CRN Lobular inflammation score (CRN-I) is defined as a decrease of at least 1 point.
Hepatocyte Balooning (CRN-B) Improvement	24 weeks	Improvement of CRN Ballooning (CRN-B) is defined as a decrease of at least 1 point.
Fibrosis (CRN-F) Improvement	24 weeks	Improvement of CRN Fibrosis score (CRN-F) is defined as a decrease of at least 1 point.
Modified ISHAK Fibrosis (ISHAK-F) Improvement	24 weeks	Improvement of Modified ISHAK Fibrosis (ISHAK-F) is defined as a decrease of at least 1 point.
Absolute Change in AST	24 weeks	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.
Absolute Change in GGT	24 weeks	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.
Absolute Change in Hs-CRP	24 weeks	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.
Absolute Change of Fasting Plasma Glucose	24 weeks	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.
Absolute Change in Haptoglobulin	24 weeks	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.
Absolute Change in Triglycerides	24 weeks	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.
Absolute Change in Apo A1	24 weeks	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.
Absolute Change in Adiponectin	24 weeks	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.
Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage	From baseline to Week 24.	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.
Absolute Change in Fibrinogen	24 weeks	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.
Absolute Change in Alpha2 Macroglobulin	24 weeks	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.
Absolute Change in HbA1c	24 weeks	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.
Absolute Change in Insulin	24 weeks	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.
Absolute Change in HOMA Index	24 weeks	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.
Absolute Change in Total Cholesterol	24 weeks	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.
Absolute Change of HDL-Cholesterol	24 weeks	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.
Absolute Change of LDL-Cholesterol	24 weeks	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.

Trial Locations

Locations (84)

North Alabama GI Research Center; 🇺🇸 Madison, Alabama, United States

ACTRI; 🇺🇸 La Jolla, California, United States

National Research Institute; 🇺🇸 Los Angeles, California, United States

Palmetto Research, LLC; 🇺🇸 Hialeah, Florida, United States

Florida Digestive Health Specialists, LLP; 🇺🇸 Lakewood Ranch, Florida, United States

Northeast GI Research Division; 🇺🇸 Concord, Massachusetts, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Carolina's Center for Liver Disease/CHG; 🇺🇸 Huntersville, North Carolina, United States

Jefferson University hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Digestive Health Research, LLC; 🇺🇸 San Antonio, Texas, United States

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