Phase 2b Study in NASH to Assess IVA337

Non-Alcoholic Steatohepatitis (NASH) Clinical Trial

— NATIVE  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03008070
• Other study ID #: IVA_01_337_HNAS_16_002
• Secondary ID: 2016-001979-70
• Status: Completed
• Phase: Phase 2
• Start date: February 7, 2017
• Est. completion date: March 16, 2020

Study information

• Verified date: July 2023
• Source: Inventiva Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 247
• Est. completion date: March 16, 2020
• Est. primary completion date: February 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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, a-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.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Non-Alcoholic Steatohepatitis (NASH)

Intervention

Drug:
• IVA337
1200mg
• IVA337
800mg
• Placebo
Placebo to match

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Inventiva Pharma

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Italy,  Mauritius,  Poland,  Slovenia,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Steatosis (CRN-S) Improvement	Improvement of CRN Steatosis score (CRN-S) is defined as a decrease of at least 1 point.	24 weeks
Secondary	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
Secondary	Hepatocyte Balooning (CRN-B) Improvement	Improvement of CRN Ballooning (CRN-B) is defined as a decrease of at least 1 point.	24 weeks
Secondary	Fibrosis (CRN-F) Improvement	Improvement of CRN Fibrosis score (CRN-F) is defined as a decrease of at least 1 point.	24 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.