Clinical trial NCT03008070: Phase 2b Study in NASH to Assess IVA337
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis (NASH)
Keywords: Non-Alcoholic Steatohepatitis
NASH
peroxisome proliferator-activated receptor (PPAR)
Liver Diseases
Fibrosis
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases
IVA337
Lead sponsor: Inventiva Pharma
Sponsor class: INDUSTRY
First posted: 2017-01-02
Enrollment: 247
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: SAF Activity Score (SAF-A) Decrease of at Least 2 Points With no Worsening of the CRN Fibrosis Score (CRN-F)
timeFrame: 24 weeks
Secondary outcomes:
measure: NASH Improvement
timeFrame: 24 weeks
measure: NASH Resolution and no Worsening of Fibrosis
timeFrame: 24 weeks
measure: Improvement of Fibrosis by at Least 1 Stage and no Worsening of NASH
timeFrame: 24 weeks
measure: Activity (SAF-A) Improvement
timeFrame: 24 weeks
measure: Steatosis (CRN-S) Improvement
timeFrame: 24 weeks
measure: Lobular Inflammation (CRN-I) Improvement
timeFrame: 24 weeks
measure: Hepatocyte Balooning (CRN-B) Improvement
timeFrame: 24 weeks
measure: Fibrosis (CRN-F) Improvement
timeFrame: 24 weeks
measure: Modified ISHAK Fibrosis (ISHAK-F) Improvement
timeFrame: 24 weeks
measure: Absolute Change in ALT
timeFrame: 24 weeks
measure: Absolute Change in AST
timeFrame: 24 weeks
measure: Absolute Change in GGT
timeFrame: 24 weeks
measure: Absolute Change in Fibrinogen
timeFrame: 24 weeks
measure: Absolute Change in Hs-CRP
timeFrame: 24 weeks
measure: Absolute Change in Alpha2 Macroglobulin
timeFrame: 24 weeks
measure: Absolute Change in Haptoglobulin
timeFrame: 24 weeks
measure: Absolute Change of Fasting Plasma Glucose
timeFrame: 24 weeks
measure: Absolute Change in Insulin
timeFrame: 24 weeks
measure: Absolute Change in HOMA Index
timeFrame: 24 weeks
measure: Absolute Change in HbA1c
timeFrame: 24 weeks
measure: Absolute Change in Total Cholesterol
timeFrame: 24 weeks
measure: Absolute Change of HDL-Cholesterol
timeFrame: 24 weeks
measure: Absolute Change of LDL-Cholesterol
timeFrame: 24 weeks
measure: Absolute Change in Triglycerides
timeFrame: 24 weeks
measure: Absolute Change in Apo A1
timeFrame: 24 weeks
measure: Absolute Change in Adiponectin
timeFrame: 24 weeks
measure: Resolution of NASH and Improvement of Fibrosis by at Least 1 Stage
timeFrame: From baseline to Week 24.
Other outcomes:
Locations:
city: Madison
country: United States
facility: North Alabama GI Research Center
state: Alabama
city: La Jolla
country: United States
facility: ACTRI
state: California
city: Los Angeles
country: United States
facility: National Research Institute
state: California
city: Hialeah
country: United States
facility: Palmetto Research, LLC
state: Florida
city: Lakewood Ranch
country: United States
facility: Florida Digestive Health Specialists, LLP
state: Florida
city: Concord
country: United States
facility: Northeast GI Research Division
state: Massachusetts
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Huntersville
country: United States
facility: Carolina's Center for Liver Disease/CHG
state: North Carolina
city: Philadelphia
country: United States
facility: Jefferson University hospital
state: Pennsylvania
city: Hermitage
country: United States
facility: Digestive Health Research, LLC
state: Tennessee
city: San Antonio
country: United States
facility: The Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Digestive Health Research, LLC
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre Department of Hepatology
city: Clayton
country: Australia
facility: Monash Medical Centre
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital & The University of Adelaide
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
city: Vienna
country: Austria
facility: Medical University Vienna
city: Brussels
country: Belgium
facility: Hopital Erasme
city: Brussels
country: Belgium
facility: Clinique Universitaire Saint-luc
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Genk
country: Belgium
facility: Ziekenhuis Oost Limburg
city: Gent
country: Belgium
facility: UZ Gent
city: Sofia
country: Bulgaria
facility: "DCC Alexandrovska", EOOD
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic Tokuda Hospital
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic University Hospital EOOD
city: Sofia
country: Bulgaria
facility: MHAT "Sveta Anna" Sofia
city: Sofia
country: Bulgaria
facility: Military Medical Academy - MHAT
city: Sofia
country: Bulgaria
facility: UMHAT "Sv. Ivan Rilski"
city: Sofia
country: Bulgaria
facility: UMHAT "Tsaritsa Yoanna-ISUL"
city: Calgary
country: Canada
facility: University of Calgary
city: Edmonton
country: Canada
facility: The Bailey Health Clinic
city: Greenfield Park
country: Canada
facility: CISSS de la Montérégie Centre
city: London
country: Canada
facility: University of Western Ontario, London Health Sciences Centre
city: Montréal
country: Canada
facility: McGill University Health Centre (MUHC)
city: Montréal
country: Canada
facility: Medpharmgene, Inc
city: Vancouver
country: Canada
facility: LAIR Centre
city: Plzen
country: Czechia
facility: Researchsite S.R.O.
city: Praha
country: Czechia
facility: Klin Med S.R.O.
city: Praha
country: Czechia
facility: Institut klinické a experimentální medicíny, IKEM
city: Angers
country: France
facility: CHU Angers
city: Besancon
country: France
facility: CHRU Besançon
city: Bordeaux
country: France
facility: Centre Hospitalier de Bordeaux
city: Créteil
country: France
facility: CHU Henri Mondor
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lyon
country: France
facility: Hôpital de La Croix Rousse
city: Montpellier
country: France
facility: Centre Hospitalier Régional Universitaire de Montpellier
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital La Pitié Salpétrière
city: Paris
country: France
facility: Hôpital Beaujon
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Strasbourg
country: France
facility: Hôpital de Hautepierre
city: Toulouse
country: France
facility: Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse
city: Aachen
country: Germany
facility: RWTH University Hospital
city: Freiburg
country: Germany
facility: Innere Medizin II - Universitätsklinik Freiburg
city: Heidelberg
country: Germany
facility: Medizinischen Klinik IV
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz, I. Med. Klinik
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Wurzburg
country: Germany
facility: University Hospital Würzburg
city: Ancona
country: Italy
facility: Ospedali Riuniti di Ancona-Università Politecnica delle Marche
city: Milano
country: Italy
facility: Granda Ospedale Maggiore Policlinico - Università di Milano
city: Palermo
country: Italy
facility: Pol. Giaccone
city: Roma
country: Italy
facility: Fondazione Policlinico Agostino Gemelli
city: San Giovanni Rotondo
country: Italy
facility: Poliambulatorio Giovanni Paolo II
city: Torino
country: Italy
facility: A.O. Città della Salute e della Scienza di Torino
city: Quatre Bornes
country: Mauritius
facility: CAP Research
city: Katowice
country: Poland
facility: Oddzial Gastroenterologii Hepatologii UCK
city: Lodz
country: Poland
facility: Katedra i Klinika Chorób Zakaźnych i Hepatologii Uniwersytetu Medycznego w Łodzi
city: Lublin
country: Poland
facility: Klinika Chorób Zakaźnych
city: Wrocław
country: Poland
facility: Centrum Badan Klinicznych
city: Celje
country: Slovenia
facility: General hospital Celje
city: Murska Sobota
country: Slovenia
facility: General Hospital Murska Sobota
city: Barcelona
country: Spain
facility: Vall d'Hebron Hospital
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro MAJADAHONDA
city: Malaga
country: Spain
facility: Virgen de la Victoria University Hospital
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Bern
country: Switzerland
facility: Universitätsklinik für Viszerale Chirurgie und Medizin
city: Lugano
country: Switzerland
facility: Epatocentro Ticino
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Freeman Hospital, Newcastle University
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
affiliation: Division of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium
name: Sven FRANCQUE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.