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

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)

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.

Study Overview

• Status: Completed
• Conditions: Non-Alcoholic Steatohepatitis (NASH)
• Intervention / Treatment: Drug: Placebo; Drug: IVA337; Drug: IVA337

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 Type: Interventional
• Enrollment (Actual): 247
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Bedford Park, Australia, SA 5042
    • Flinders Medical Centre Department of Hepatology
  • Clayton, Australia, 3168
    • Monash Medical Centre
  • Elizabeth Vale, Australia, SA 5112
    • Lyell McEwin Hospital & The University of Adelaide
  • Herston, Australia
    • Royal Brisbane and Women's Hospital
  • Murdoch, Australia, WA 6150
    • Fiona Stanley Hospital
• Austria
  • Vienna, Austria, 1090
    • Medical University Vienna
• Belgium
  • Brussels, Belgium, 1070
    • Hopital Erasme
  • Brussels, Belgium, 1200
    • Clinique Universitaire Saint-Luc
  • Edegem, Belgium, 2650
    • Antwerp University Hospital
  • Genk, Belgium
    • Ziekenhuis Oost Limburg
  • Gent, Belgium
    • UZ Gent
• Bulgaria
  • Sofia, Bulgaria
    • Acibadem City Clinic Tokuda Hospital
  • Sofia, Bulgaria
    • "DCC Alexandrovska", EOOD
  • Sofia, Bulgaria
    • Acibadem City Clinic University Hospital EOOD
  • Sofia, Bulgaria
    • MHAT "Sveta Anna" Sofia
  • Sofia, Bulgaria
    • Military Medical Academy - MHAT
  • Sofia, Bulgaria
    • UMHAT "Sv. Ivan Rilski"
  • Sofia, Bulgaria
    • UMHAT "Tsaritsa Yoanna-ISUL"
• Canada
  • Calgary, Canada
    • University of Calgary
  • Edmonton, Canada
    • The Bailey Health Clinic
  • Greenfield Park, Canada
    • CISSS de la Montérégie Centre
  • London, Canada
    • University of Western Ontario, London Health Sciences Centre
  • Montréal, Canada
    • McGill University Health Centre (MUHC)
  • Montréal, Canada
    • Medpharmgene, Inc
  • Vancouver, Canada
    • Lair Centre
• Czechia
  • Plzen, Czechia, 30100
    • Researchsite s.r.o.
  • Praha, Czechia, 1200
    • Klin Med S.R.O.
  • Praha, Czechia, 14021
    • Institut klinické a experimentální medicíny, IKEM
• France
  • Angers, France, 49933
    • CHU Angers
  • Besancon, France, 25000
    • CHRU Besançon
  • Bordeaux, France
    • Centre Hospitalier de Bordeaux
  • Créteil, France
    • CHU Henri Mondor
  • Grenoble, France
    • Chu de Grenoble
  • Lyon, France
    • Hopital de la Croix Rousse
  • Montpellier, France
    • Centre Hospitalier Régional Universitaire de Montpellier
  • Nice, France, 06202
    • Chu de Nice
  • Paris, France, 75012
    • Hôpital Saint Antoine
  • Paris, France, 75013
    • Hôpital La Pitié Salpêtrière
  • Paris, France
    • Hopital Beaujon
  • Rennes, France
    • Centre Hospitalier Universitaire de Rennes
  • Strasbourg, France
    • Hopital de Hautepierre
  • Toulouse, France
    • Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse
• Germany
  • Aachen, Germany, 52074
    • RWTH University Hospital
  • Freiburg, Germany
    • Innere Medizin II - Universitätsklinik Freiburg
  • Heidelberg, Germany, 69120
    • Medizinischen Klinik IV
  • Mainz, Germany, 55131
    • Universitätsmedizin Mainz, I. Med. Klinik
  • Münster, Germany
    • Universitätsklinikum Münster
  • Wurzburg, Germany, 97080
    • University Hospital Würzburg
• Italy
  • Ancona, Italy, 60126
    • Ospedali Riuniti di Ancona-Università Politecnica delle Marche
  • Milano, Italy, 20122
    • Granda Ospedale Maggiore Policlinico - Università di Milano
  • Palermo, Italy, 90127
    • Pol. Giaccone
  • Roma, Italy, 00168
    • Fondazione Policlinico Agostino Gemelli
  • San Giovanni Rotondo, Italy
    • Poliambulatorio Giovanni Paolo II
  • Torino, Italy, 10126
    • A.O. Città della Salute e della Scienza di Torino
• Mauritius
  • Quatre Bornes, Mauritius
    • CAP Research
• Poland
  • Katowice, Poland
    • Oddzial Gastroenterologii Hepatologii UCK
  • Lodz, Poland, 91-347
    • Katedra i Klinika Chorób Zakaźnych i Hepatologii Uniwersytetu Medycznego w Łodzi
  • Lublin, Poland, 20-081
    • Klinika Chorób Zakaźnych
  • Wrocław, Poland
    • Centrum Badan Klinicznych
• Slovenia
  • Celje, Slovenia
    • General Hospital Celje
  • Murska Sobota, Slovenia
    • General Hospital Murska Sobota
• Spain
  • Barcelona, Spain
    • Vall d'Hebron Hospital
  • Madrid, Spain, 28222
    • Hospital Puerta de Hierro Majadahonda
  • Malaga, Spain, 29010
    • Virgen de la Victoria University Hospital
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocio
• Switzerland
  • Bern, Switzerland
    • Universitätsklinik für Viszerale Chirurgie und Medizin
  • Lugano, Switzerland, 6900
    • Epatocentro Ticino
• United Kingdom
  • London, United Kingdom
    • Kings College Hospital NHS Foundation Trust
  • Newcastle, United Kingdom, NE7 7DN
    • Freeman Hospital, Newcastle University
  • Nottingham, United Kingdom
    • Nottingham University Hospitals NHS Trust
• United States
  • Alabama
    • Madison, Alabama, United States, 35758
      • North Alabama GI Research Center
  • California
    • La Jolla, California, United States, 92037
      • ACTRI
    • Los Angeles, California, United States, 90057
      • National Research Institute
  • Florida
    • Hialeah, Florida, United States, 33016
      • Palmetto Research, LLC
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Digestive Health Specialists, LLP
  • Massachusetts
    • Concord, Massachusetts, United States, 29027
      • Northeast GI Research Division
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Huntersville, North Carolina, United States, 28078
      • Carolina's Center for Liver Disease/CHG
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson University Hospital
  • Tennessee
    • Hermitage, Tennessee, United States, 37076
      • Digestive Health Research, LLC
  • Texas
    • San Antonio, Texas, United States, 78215
      • The Texas Liver Institute
    • San Antonio, Texas, United States, 78229
      • Digestive Health Research, LLC
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IVA337 1200mg; IVA337 400mg, once a day (Quaque Die, QD) with food	Drug: IVA337; 1200mg; Drug: IVA337; 800mg
Experimental: IVA337 800mg; IVA337 400mg, once a day (Quaque Die, QD) with food	Drug: IVA337; 1200mg; Drug: IVA337; 800mg
Placebo Comparator: Placebo; Placebo to match, once a day (Quaque Die, QD) with food	Drug: Placebo; Placebo to match

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Inventiva Pharma
• Investigators: Principal Investigator: Sven FRANCQUE, MD, PhD, Division of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium

Publications and helpful links

General Publications

• Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, Loomba R, Harrison SA, Balabanska R, Mateva L, Lanthier N, Alkhouri N, Moreno C, Schattenberg JM, Stefanova-Petrova D, Vonghia L, Rouzier R, Guillaume M, Hodge A, Romero-Gomez M, Huot-Marchand P, Baudin M, Richard MP, Abitbol JL, Broqua P, Junien JL, Abdelmalek MF; NATIVE Study Group. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med. 2021 Oct 21;385(17):1547-1558. doi: 10.1056/NEJMoa2036205.
• Sven M F, Pierre B, Manal F A, Quentin M A, Elisabetta B, Vlad R, Philippe HM, Bruno S, Jean-Louis J, Pierre B, Jean-Louis A. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study. Contemp Clin Trials. 2020 Nov;98:106170. doi: 10.1016/j.cct.2020.106170. Epub 2020 Oct 8.

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2017
• Primary Completion (Actual): February 20, 2020
• Study Completion (Actual): March 16, 2020

Study Registration Dates

• First Submitted: December 22, 2016
• First Submitted That Met QC Criteria: December 28, 2016
• First Posted (Estimated): January 2, 2017

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Fibrosis; Digestive System Diseases; NASH; Liver Diseases; Fatty Liver; Non-Alcoholic Steatohepatitis; IVA337; peroxisome proliferator-activated receptor (PPAR); Non-alcoholic Fatty Liver Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: IVA_01_337_HNAS_16_002; 2016-001979-70 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No