A Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 )

Study Overview
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Brief Summary
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This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis histological stage F2 or F3

Detailed Description
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Primary objectives This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage F2 or F3 and consists of 2 sequential parts - an initial double-blind placebo-controlled (DBPC) period (Part A) followed by a double-blind active treatment extension (ATE) period (Part B), with the following primary objectives: Part A To assess the safety and efficacy of lanifibranor compared to placebo on 'NASH resolution and improvement of fibrosis' assessed by liver histology. Part B To assess the safety of lanifibranor beyond the DBPC period. Secondary objectives Key secondary objectives of Part 1: To assess the effect of lanifibranor compared to placebo on NASH resolution and no worsening of fibrosis To assess the effect of lanifibranor compared to placebo on improvement of fibrosis with no worsening of NASH Other secondary objectives of both Part 1 and Part 2: To assess the effect of lanifibranor on other key histological features of NASH (only for DBPC period) To assess the effect of lanifibranor on NASH resolution and improvement of fibrosis in diabetic patients (only for DBPC period) To assess the effect of lanifibranor on liver tests To assess the effect of lanifibranor on glycaemic parameters To assess the effect of lanifibranor on lipid parameters To assess the effect of lanifibranor on liver stiffness and steatosis assessed by elastography. To assess the effect of lanifibranor on health-related quality of life To assess the safety of lanifibranor To assess population PK modeling through plasma levels of lanifibranor using sparse sampling scheme (only for DBPC period)

Official Title
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A Randomised, Double-blind, Placebo-controlled, Multicentre, Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) and Fibrosis Stages F2 and F3

Conditions
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NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: IVA337
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Prescreening Criteria: Diagnosed with NASH on prior liver biopsy Type 2 diabetes with high waist circumference or obesity or hepatic steatosis on ultrasound At least 3 of the components of metabolic syndrome Inclusion Criteria: Male or female, aged ≥18 years at the time of signing informed consent Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF): Steatosis score ≥1 Activity score: A3 or A4 Fibrosis score: F2 or F3 No qualitative change in dose for the drugs listed below: Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists) or sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors): for at least 3 months Vitamin E (if at a dose ≥400 IU/day): for at least 6 months Statins: for at least 3 months No qualitative change in dose for all other chronically administered drugs for at least 3 months prior to Screening Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods) Negative serum pregnancy test at study Screening for females of childbearing potential confirmed by central laboratory. Females of childbearing potential must practice a consistent and proper use of highly effective method of contraception throughout the study and for 1 month after treatment discontinuation. Exclusion Criteria: Liver-related: Documented causes of chronic liver disease other than NASH Histologically documented liver cirrhosis (fibrosis stage F4) History or current diagnosis of hepatocellular carcinoma (HCC) History of or planned liver transplant Positive human immunodeficiency virus (HIV) serology ALT or AST >5 × ULN AST<0.6 ULN if the liver biopsy has to be performed in the scope of the study Abnormal synthetic liver function as defined by Screening central laboratory evaluation Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males Patient currently receiving any approved treatment for NASH or obesity Current or recent history (<5 years) of significant alcohol consumption Treatment with drugs that may cause non-alcoholic fatty liver disease (NAFLD) administered for at least 2 weeks within 12 months prior to qualifying liver biopsy Glycaemia related: HbA1c >9% at Screening Diabetes mellitus other than type 2 Current treatment with insulin Treatment with PPAR-gamma agonists (thiazolidinediones [TZDs]) 12 months before screening or historical biopsy. Obesity related: Bariatric surgery: Restrictive procedures are allowed, if performed >6 months prior to the qualifying liver biopsy; malabsorptive procedures and procedures combining both restrictive and malabsorptive methods are not allowed within 5 years of the qualifying liver biopsy. Cardiovascular related: History of heart failure with reduced left ventricular ejection fraction (LVEF) Atrial fibrillation requiring anticoagulation Unstable heart failure Uncontrolled hypertension at Screening (values >160/100 mm Hg) General safety: Women currently breastfeeding Previous exposure to lanifibranor Participation in any clinical trial investigational medicinal product/device within 3 months from Screening or 5 half-lives from Screening, whichever is longer Concomitant treatment with PPAR-alpha agonists (fibrates)

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: Lanifibranor (IVA 337) (800 mg/day)<br>2 Lanifibranor tablets 400mg + 1 Placebo to match tablet with food --> once a day (quaque die, QD) | Drug: IVA337<br>* A total of 1000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part A and Part B.<br>* Other names: Lanifibranor;Drug: Placebo<br>* A total of 1000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part A and Part B.<br>|
| Experimental: Lanifibranor (IVA 337) (1200 mg/day)<br>3 Lanifibranor tablets 400mg with food --> once a day (quaque die, QD) | Drug: IVA337<br>* A total of 1000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part A and Part B.<br>* Other names: Lanifibranor;|
| Placebo Comparator: Matching placebo<br>3 Placebo to match tablets with food --> once a day (quaque die, QD) | Drug: Placebo<br>* A total of 1000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part A and Part B.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of NASH and improvement of fibrosis | Part A: DBPC: Resolution of NASH and improvement of fibrosis at Week 72, defined by NASH CRN scores for ballooning of 0 and inflammation of 0 to 1, and fibrosis score ≥1 stage decrease compared to Baseline | Part A: Date of randomisation until the date of biopsy at Week 72 | 
| Safety Analyses | Part B: ATE: Using the DBPC on-treatment period, comparing the 2 active arms versus placebo Using the DBPC +ATE on treatment periods, assessing the 2 active arms. For adverse events, adjudicated liver events, and DILI and MACE events, in addition to the raw cumulative incidence proportions, the exposure-adjusted incidence rates will be provided based on the time patients are at risk. | 48 weeks after completion of DBPC period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase III, Nonalcoholic Steatohepatitis, NASH, Peroxisome proliferator-activated receptor (PPAR), Liver Diseases, Fibrosis