Phase 2b Study in NASH to Assess IVA337
- Conditions
- Non-Alcoholic Steatohepatitis (NASH)
- Interventions
- Drug: IVA337Drug: 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 247
-
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.
- 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 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 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 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)
Hopital Erasme
🇧🇪Brussels, Belgium
Klinika Chorób Zakaźnych
🇵🇱Lublin, Poland
General Hospital Murska Sobota
🇸🇮Murska Sobota, Slovenia
Acibadem City Clinic Tokuda Hospital
🇧🇬Sofia, Bulgaria
Military Medical Academy - MHAT
🇧🇬Sofia, Bulgaria
UMHAT "Sv. Ivan Rilski"
🇧🇬Sofia, Bulgaria
Katedra i Klinika Chorób Zakaźnych i Hepatologii Uniwersytetu Medycznego w Łodzi
🇵🇱Lodz, Poland
Centrum Badan Klinicznych
🇵🇱Wrocław, Poland
General hospital Celje
🇸🇮Celje, Slovenia
"DCC Alexandrovska", EOOD
🇧🇬Sofia, Bulgaria
MHAT "Sveta Anna" Sofia
🇧🇬Sofia, Bulgaria
CAP Research
🇲🇺Quatre Bornes, Mauritius
Oddzial Gastroenterologii Hepatologii UCK
🇵🇱Katowice, Poland
Clinique Universitaire Saint-luc
🇧🇪Brussels, Belgium
Antwerp University Hospital
🇧🇪Edegem, Belgium
Flinders Medical Centre Department of Hepatology
🇦🇺Bedford Park, Australia
Royal Brisbane and Women's Hospital
🇦🇺Herston, Australia
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Monash Medical Centre
🇦🇺Clayton, Australia
UZ Gent
🇧🇪Gent, Belgium
Lyell McEwin Hospital & The University of Adelaide
🇦🇺Elizabeth Vale, Australia
Fiona Stanley Hospital
🇦🇺Murdoch, Australia
Medical University Vienna
🇦🇹Vienna, Austria
UMHAT "Tsaritsa Yoanna-ISUL"
🇧🇬Sofia, Bulgaria
Researchsite S.R.O.
🇨🇿Plzen, Czechia
Centre Hospitalier Régional Universitaire de Montpellier
🇫🇷Montpellier, France
Vall d'Hebron Hospital
🇪🇸Barcelona, Spain
Virgen de la Victoria University Hospital
🇪🇸Malaga, Spain
Universitätsklinik für Viszerale Chirurgie und Medizin
🇨🇭Bern, Switzerland
Epatocentro Ticino
🇨🇭Lugano, Switzerland
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, United Kingdom
CISSS de la Montérégie Centre
🇨🇦Greenfield Park, Canada
University of Western Ontario, London Health Sciences Centre
🇨🇦London, Canada
Medpharmgene, Inc
🇨🇦Montréal, Canada
LAIR Centre
🇨🇦Vancouver, Canada
CHU Angers
🇫🇷Angers, France
CHRU Besançon
🇫🇷Besancon, France
Centre Hospitalier de Bordeaux
🇫🇷Bordeaux, France
CHU de Grenoble
🇫🇷Grenoble, France
CHU de Nice
🇫🇷Nice, France
Hôpital Beaujon
🇫🇷Paris, France
Centre Hospitalier Universitaire de Rennes
🇫🇷Rennes, France
Institut klinické a experimentální medicíny, IKEM
🇨🇿Praha, Czechia
North Alabama GI Research Center
🇺🇸Madison, Alabama, United States
ACTRI
🇺🇸La Jolla, California, United States
Florida Digestive Health Specialists, LLP
🇺🇸Lakewood Ranch, Florida, United States
Carolina's Center for Liver Disease/CHG
🇺🇸Huntersville, North Carolina, United States
Northeast GI Research Division
🇺🇸Concord, Massachusetts, United States
Ziekenhuis Oost Limburg
🇧🇪Genk, Belgium
Acibadem City Clinic University Hospital EOOD
🇧🇬Sofia, Bulgaria
University of Calgary
🇨🇦Calgary, Canada
McGill University Health Centre (MUHC)
🇨🇦Montréal, Canada
Klin Med S.R.O.
🇨🇿Praha, Czechia
CHU Henri Mondor
🇫🇷Créteil, France
Hôpital de La Croix Rousse
🇫🇷Lyon, France
Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse
🇫🇷Toulouse, France
Hôpital Saint Antoine
🇫🇷Paris, France
Innere Medizin II - Universitätsklinik Freiburg
🇩🇪Freiburg, Germany
Hôpital La Pitié Salpétrière
🇫🇷Paris, France
Medizinischen Klinik IV
🇩🇪Heidelberg, Germany
Universitätsmedizin Mainz, I. Med. Klinik
🇩🇪Mainz, Germany
Universitätsklinikum Münster
🇩🇪Münster, Germany
University Hospital Würzburg
🇩🇪Wurzburg, Germany
Ospedali Riuniti di Ancona-Università Politecnica delle Marche
🇮🇹Ancona, Italy
Granda Ospedale Maggiore Policlinico - Università di Milano
🇮🇹Milano, Italy
A.O. Città della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Fondazione Policlinico Agostino Gemelli
🇮🇹Roma, Italy
Pol. Giaccone
🇮🇹Palermo, Italy
Poliambulatorio Giovanni Paolo II
🇮🇹San Giovanni Rotondo, Italy
Hospital Universitario Marqués de Valdecilla
🇪🇸Santander, Spain
Hospital Puerta de Hierro MAJADAHONDA
🇪🇸Madrid, Spain
Hospital Virgen del Rocío
🇪🇸Sevilla, Spain
Freeman Hospital, Newcastle University
🇬🇧Newcastle, United Kingdom
Kings College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
RWTH University Hospital
🇩🇪Aachen, Germany
The Bailey Health Clinic
🇨🇦Edmonton, Canada
Hôpital de Hautepierre
🇫🇷Strasbourg, France
National Research Institute
🇺🇸Los Angeles, California, United States
Palmetto Research, LLC
🇺🇸Hialeah, Florida, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Jefferson University hospital
🇺🇸Philadelphia, Pennsylvania, United States
Digestive Health Research, LLC
🇺🇸San Antonio, Texas, United States
The Texas Liver Institute
🇺🇸San Antonio, Texas, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
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