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Phase 2b Study in NASH to Assess IVA337 (NATIVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03008070
Recruitment Status : Completed
First Posted : January 2, 2017
Last Update Posted : April 16, 2020
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Non-Alcoholic Steatohepatitis (NASH) Drug: IVA337 Drug: Placebo Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 247 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : February 7, 2017
Actual Primary Completion Date : February 20, 2020
Actual Study Completion Date : March 16, 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: IVA337 1200mg
IVA337 400mg, once a day (Quaque Die, QD) with food
Drug: IVA337

Experimental: IVA337 800mg
IVA337 400mg, once a day (Quaque Die, QD) with food
Drug: IVA337

Placebo Comparator: Placebo
Placebo to match, once a day (Quaque Die, QD) with food
Drug: Placebo
Placebo to match

Primary Outcome Measures :
  1. Responder analysis based on the improvement of the SAF (steatosis: S, activity : A, and fibrosis: F) activity score. [ Time Frame: 24 weeks ]
    Responder is defined as a decrease from Baseline of at least 2 points of the SAF activity score combining hepatocellular inflammation and ballooning without worsening of fibrosis

Secondary Outcome Measures :
  1. Percent of patients with resolution of NASH from baseline to end of treatment [ Time Frame: 24 weeks ]
  2. Percent of patients with a change in components of SAF score from baseline to end of treatment : Steatosis, Lobular inflammation, Ballooning, Fibrosis [ Time Frame: 24 weeks ]
  3. Change in fibrosis score on a 4-points scale (SAF score) from baseline to end of treatment [ Time Frame: 24 weeks ]
  4. Change in fibrosis score on modified Ishak score from baseline to end of treatment [ Time Frame: 24 weeks ]
  5. Liver enzymes change from baseline to end of treatment [ Time Frame: 24 weeks ]
    Alanine amino transferase (ALT), Aspartate amino transferase (AST), Gamma glutamyl transpeptidase (γGT)

  6. Inflammatory markers change from baseline to end of treatment [ Time Frame: 24 weeks ]
    fibrinogen, High-sensitivity C-reactive protein (hs-CRP), alpha2 macroglobulin and haptoglobin

  7. Glucose metabolism change from baseline to end of treatment [ Time Frame: 24 weeks ]
    (fasting glucose and insulin, Homeostasis model assessment of insulin resistance (HOMA) index and, in subjects with type 2 diabetes mellitus (T2DM), HbA1c

  8. Main plasma lipids levels change from baseline to end of treatment [ Time Frame: 24 weeks ]
    Total cholesterol (TC), High-density lipoprotein cholesterol (HDL-C), calculated Low density lipoprotein cholesterol (LDL-C), Triglycerides (TG) and apoA1

  9. Adiponectin change from baseline to end of treatment [ Time Frame: 24 weeks ]

Other Outcome Measures:
  1. Exploratory biomarkers change from baseline to end of treatment [ Time Frame: 24 weeks ]
    inflammation, lipids, glucides, fibrosis, bone remodeling

  2. Transient Elastography (TE) and Controlled Attenuation Parameter (CAP) change from baseline to end of treatment [ Time Frame: 24 weeks ]
  3. If deemed necessary: Immunohistochemistry: change in the semi quantitative score of ballooning and stellate cell activation from baseline to end of treatment [ Time Frame: 24 weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03008070

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Sponsors and Collaborators
Inventiva Pharma
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Principal Investigator: Sven FRANCQUE, MD, PhD Division of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium
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Responsible Party: Inventiva Pharma Identifier: NCT03008070    
Other Study ID Numbers: IVA_01_337_HNAS_16_002
2016-001979-70 ( EudraCT Number )
First Posted: January 2, 2017    Key Record Dates
Last Update Posted: April 16, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Inventiva Pharma:
Non-Alcoholic Steatohepatitis
peroxisome proliferator-activated receptor (PPAR)
Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases