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)

• Register: EUCTR
• Last refreshed on: 2 June 2020
• Main ID: EUCTR2016-001979-70-BE
• Date of registration: 23/09/2016
• Prospective Registration: Yes
• Primary sponsor: Inventiva S.A.
• Public 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)
• Scientific 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)
• Date of first enrolment: 23/01/2017
• Target sample size: 225
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001979-70
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Bulgaria, Canada, Czech Republic, France, Germany, Italy, Mauritius, Netherlands, Poland, Portugal, Slovenia, Spain, Switzerland, United Kingdom

Contacts

• Name: Mathilde Merot, Regulatory Affairs
• Affiliation: INVENTIVA S.A.

• Name: Mathilde Merot, Regulatory Affairs
• Affiliation: INVENTIVA S.A.

Key inclusion & exclusion criteria

Inclusion criteria:
-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 on entry into protocol:
oALT < 10N
oHemoglobin > 11 g/dL for females and > 12 g/dL for males
oWhite blood cell (WBC) > 2.5 K/µL
oNeutrophil count > 1.5 K/µL
oPlatelets > 100 K/µL
oTotal bilirubin < 35µmol/L. Patients with bilirubin > 35µmol/L can be included if non-conjugated bilirubin in the setting of a Gilbert syndrome.
oAlbumin > 36 g/L
o International Normalized Ratio (INR) < 1.4
oSerum creatinin <1.3 mg/dL (men) or <1.1 (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…)
-If applicable, have a stable type 2 diabetes, defined as HgbA1c < 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.

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

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/day) for females.
-Unstable metabolic condition: Weight change > 5kg 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 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 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/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, including myocardial infarction, except patients with only well controlled hypertension. Any clinically significant ECG abnormality reported by central ECG reading
-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: 18.Lactose monohydrate, Hypromellose, Sodium laurilsulfate, Sodium starch glycolate (type A), Magnesium stearate, Opadry™ II 85F18422
-Be possibly dependent on the Investigator or the Sponsor (eg, including, but not limited to, affiliated employee).
- Creatine phosphokinase (CPK)>5 x ULN
- Osteopenia or any other well documented Bone disease. Patient whitout 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Nonalcoholic steatohepatitis (NASH)
MedDRA version: 20.1 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Intervention(s)

Product Name: Lanifibranor
Product Code: IVA337
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Not Available
CAS Number: 927961-18-0
Current Sponsor code: IVA337
Other descriptive name: 1-(6-BENZOTHIAZOLYLSULFONYL)-5-CHLORO-1H-INDOLE-2-BUTANOIC ACID
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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(s)

Timepoint(s) of evaluation of this end point: From baseline to 24 weeks of treatment

Secondary end point(s): The following changes from baseline to 24 weeks of treatment will be evaluated:
•NASH improvers defined as subjects with a decrease of at least 2 points in NAS, and no worsening in fibrosis in NASH from baseline to end of treatment (week 24).
•Percent of patients with reversal of NASH (Steatosis without ballooning and with or without mild inflammation and no worsening of fibrosis) from baseline to end of treatment (week 24).
•Percent of patients with a change in components of SAF score from baseline to end of treatment (week 24):
-Steatosis: -1 point
-Lobular inflammation: -1 point
-Balloonning: -1 point
•Immunohistochemistry: change in the semiquantitative score of ballooning and stellate cell activation from baseline to end of treatment (week 24).
•Change in fibrosis score on a 4-point scale (SAF) and modified Ishak: - 1 point from baseline to end of treatment (week 24). Comparison of mean change in fibrosis area assessed by morphometry (CPA) from baseline to end of treatment (week 24).
•Liver enzymes (ALT, AST, ?GT) change from baseline to end of treatment (week 24).
•Inflammatory markers (fibrinogen, hs-CRP, alpha2 macroglobulin and haptoglobin levels) change from baseline to end of treatment (week 24).
•Glucose metabolism (fasting glucose and insulin, HOMA index and, in subjects with T2DM, HbA1c) change from baseline to end of treatment (week 24).
•Main plasma lipids levels (TC, HDL-C, calculated LDL-C, TG and apoA1) change from baseline to end of treatment (week 24).
•Adiponectin change from baseline to end of treatment (week 24).

Secondary ID(s)

IVA_01_337_HNAS_16_002

Source(s) of Monetary Support

Inventiva S.A.

Ethics review

Status: Approved
Approval date: 23/01/2017
Contact: