Non-alcoholic Steatohepatitis (NASH) MedDRA version: 22.0 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Sponsors
Inventiva S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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
Exclusion criteria
Exclusion criteria: 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 2 × ULN 13. Patient currently receiving any approved treatment for NASH or obesity 14. Current or recent history (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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis assessed by liver histology. Part 2 To assess the effect of lanifibranor compared to placebo on delaying NASH disease progression measured by a composite endpoint that includes progression to cirrhosis, liver-related clinical outcome events, or all-cause death. ;Secondary Objective: Key secondary objectives of Part 1 • To assess the effect of lanifibranor compared to placebo on NASH resolution and no worsening of fibrosis • To assess the effect of lanifibranor compared to placebo on improvement of fibrosis with no worsening of NASH. Other secondary objectives of both Part 1 and Part 2: • To assess the effect of lanifibranor compared to placebo on other key histological features of NASH • To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis in diabetic patients • To assess the effect of lanifibranor compared to placebo on liver function tests, glycaemic parameters, lipid parameters and liver stiffness • To assess the effect of lanifibranor compared to placebo on health-related quality of life • To assess the long-term safety of lanifibranor • To assess the population PK modeling of trough plasma levels of lanifibranor ;Primary end point(s): Part 1 Resolution of NASH and improvement of fibrosis at Week 72, defined by NASH CRN scores for ballooning of 0 and inflammation of 0 to 1, and fibrosis score =1 stage decrease compared to Baseline. Part 2 Time to first clinical outcome event; defined as a composite endpoint of any of the following: • Histological progression to cirrhosis (defined as histological confirmation of fibrosis score CRN F4) • All-cause mortality • Liver transplant • MELD score =15 • New onset ascites requiring treatment • Overnight hospitalisation due to hepatic decompensation event(s) including: oHepatic encephalopathy Grade =2 (as assessed by West Haven scale) oVariceal bl | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Resolution of NASH and no worsening of fibrosis at Week 70, defined by NASH CRN scores for ballooning of 0, inflammation of 0 to 1, and no fibrosis score increased compared to Baseline. Improvement of fibrosis and no worsening of NASH, defined by a decrease in NASH CRN fibrosis score =1 stage from Baseline and no increase in scores for ballooning, inflammation, or steatosis. Resolution of NASH and improvement of fibrosis at Week 72 and End of Study (EoS). Resolution of NASH and no worsening of fibrosis at Week 72 and EoS. Improvement of fibrosis and no worsening of NASH at Week 72 and EoS. Improvement of NASH CRN fibrosis stage by at least 2 points and no worsening of NASH (no increase in scores for steatosis, ballooning, or lobular inflammation) at Week 72 and EoS. Resolution of fibrosis, defined as NASH CRN fibrosis stage 0, at Week 72 and EoS. Improvement in NAFLD Activity Score (NAS) by at least 2 points (at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning) and no worsening of fibrosis at Week 72 and EoS. Improvement of each histological feature of NASH by at least 1 point (steatosis, lobular inflammation, hepatocellular ballooning) and no worsening of fibrosis at Week 72 and EoS. NASH resolution and improvement of fibrosis at Week 72 and EoS, in the subgroup of diabetics. Change from Baseline in liver function tests (AST, ALT, GGT, ALP, direct and total bilirubin). Change from Baseline in liver stiffness by elastography (only at sites with suitable equipment). ;Timepoint(s) of evaluation of this end point: Part 1 : Date of randomisation until the date of biopsy at Week 72 visit. Part 2: Date of randomisation until the EoS date. | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Norway, Poland, Portugal, Romania, South Africa, Spain, Sweden, Ukraine, United Kingdom, United States
Contacts
Public ContactMartine Baudin
Inventiva S.A.
Outcome results
None listed