A randomised, double-blind, placebo-controlled, multicentre, Phase 3 study evaluating long-term efficacy and safety of lanifibranor in adult patients with non-cirrhotic non-alcoholic steatohepatitis (NASH) and fibrosis 2 (F2)/fibrosis 3 (F3) stage of liver fibrosis - NATIV3
- Conditions
- on-alcoholic Steatohepatitis (NASH)MedDRA version: 22.0Level: PTClassification code 10053219Term: Non-alcoholic steatohepatitisSystem Organ Class: 10019805 - Hepatobiliary disordersTherapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]
- Registration Number
- EUCTR2020-004986-38-ES
- Lead Sponsor
- Inventiva S.A.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 2000
1. Able to understand the nature of the study, willing and able to comply with the study procedures and restrictions, and ableto provide signed, dated and written informed consent obtained before any study-related activities, sampling or analysis.
2. The patient will be willing to continue on the study in case of moving or relocation during the first 72 weeks of the study.
3. Male or female, aged =18 years at the time of signing informed consent
4. If biopsy performed before Screening, histological diagnosis of NASH with liver fibrosis made no more than 6 months before Screening
5. Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF):
a.Steatosis score =1
b.Activity score: A3 or A4
c.Fibrosis score: F2 or F3
6. Model for End-Stage Liver Disease (MELD) score =12
7. Stable dose for the specified period is required prior to the historical liver biopsy or before Screening visit (whichever is longer) until Baseline visit (Visit 0) for the drugs listed below:
a.Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists) or sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors): Stable dose for at least 3 months
b.Vitamin E (if at a dose =400 IU/day): Stable dose for at least 6 months
c.Statins: Stable dose for at least 3 months
8. All chronically administered drugs not covered by criterion #7 (including but not limited to antidiabetic treatments other than GLP1 receptor agonists and SGLT2 inhibitors, antihypertensives, antidepressants, cardiovascular, antihyperlipidemic, etc) must be stable for at least 3 months prior to Screening
9. History of at least 1 unsuccessful attempt to reduce body weight by diet and/or exercise within the past 6 years up to 6 months prior to Screening
10. Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods)
11. No attempt to change lifestyle (diet and/or exercise) during the 3 months prior to Screening
12. Patient agrees to follow recommendations with lifestyle modifications, which will be monitored throughout the whole study period.
13. 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. Highly effective contraceptive methods are defined as follows: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, and sexual abstinence.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1800
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 200
Liver-related:
1. Documented causes of chronic liver disease other than NASH including, but not restricted to:
a.Viral hepatitis, unless eradicated at least 3 years prior to Screening
b.Drug-induced liver disease
c.Alcoholic liver disease
d.Autoimmune hepatitis
e.Wilson’s disease
f.Haemochromatosis
g.Primary biliary cholangitis
h.Primary sclerosing cholangitis
i.Alpha-1-antitrypsin deficiency
2. Histologically documented liver cirrhosis (fibrosis stage F4), either at Screening or in a historical biopsy or diagnosis of cirrhosis based on clinic biochemical and imaging criteria
3. History or current diagnosis of hepatocellular carcinoma HCC
4. History of or planned liver transplant
5. Inability or unwillingness to undergo a liver biopsy at Screening (if a suitable historical biopsy is unavailable for central review), at Week 72, and after the non-invasive algorithm suggests high risk of progression to F4 OR at the End of Study)
6. Positive human immunodeficiency virus (HIV) serology
7. ALT or AST >5 × ULN
8. Abnormal synthetic liver function as defined by Screening central laboratory evaluation of any of the following:
a.Albumin below the lower limit of the normal range
b.International normalised ratio (INR) =1.3 (unless patient is on anticoagulants)
c.Total bilirubin level =1.3 mg/dL (22.2 µmol/L) (patients with a documented history of Gilbert’s syndrome can be enrolled if the direct bilirubin is within normal reference range)
9. Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males
10. White blood cell (WBC) count <5.0 × 10^9/L (<5.0 × 10^3/µL)
11. Platelet count <150,000/µL
12. Alkaline phosphatase (ALP) >2 × ULN
13. Patient currently receiving any approved treatment for NASH or obesity
14. Current or recent history (<5 years) of significant alcohol consumption, which is typically defined as higher than 30 g pure alcohol per day for men and as higher than 20 g pure alcohol per day for women
15. 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:
16. HbA1c >9% at Screening
17. Diabetes mellitus other than type 2
18. Current treatment with insulin
19. Previous or current treatment with PPAR-gamma agonists
20. Obesity related:
21. Bariatric surgery: Restrictive procedures (e.g. lap banding, intragastric balloon, sleeve gastrectomy) are allowed, if performed >6 months prior to the qualifying liver biopsy; malabsorptive procedures (e.g. biliopancreatic diversion) and procedures combining both restrictive and malabsorptive methods (e.g. Roux-en-Y gastric bypass, duodenal switch surgery) are not allowed within 5 years of the qualifying liver biopsy. Liposuction and/or abdominoplasty are allowed if performed >6 months before qualifying liver biopsy. Planned bariatric surgery is not allowed
22. Participation in an organised weight-loss programme within 3 months of the study, or planned participation through Week 72
23. Cardiovascular related:
24. History of heart failure with reduced left ventricular ejection fraction (LVEF) defined as any past measurement of LVEF = 40%
25. N-terminal-prohormone B-type natriuretic peptide (NT-proBNP) >900 pg/mL
26. Atrial fibrillation requiring anticoagulation
27. Unstable heart failure with preserved ejection fraction
28. Any other clinical significant cardiovascular event requiring hospitalisation within 6 months before Screening
29. Uncontrolled hyper
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method