NASH - Nonalcoholic Steatohepatitis
Conditions
Keywords
Phase III, Nonalcoholic Steatohepatitis, NASH, Peroxisome proliferator-activated receptor (PPAR), Liver Diseases, Fibrosis
Brief summary
This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis histological stage F2 or F3
Detailed description
Primary objectives This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage F2 or F3 and consists of 2 sequential parts - an initial double-blind placebo-controlled (DBPC) period (Part A) followed by a double-blind active treatment extension (ATE) period (Part B), with the following primary objectives: Part A To assess the safety and efficacy of lanifibranor compared to placebo on 'NASH resolution and improvement of fibrosis' assessed by liver histology. Part B To assess the safety of lanifibranor beyond the DBPC period. Secondary objectives 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 on other key histological features of NASH (only for DBPC period) * To assess the effect of lanifibranor on NASH resolution and improvement of fibrosis in diabetic patients (only for DBPC period) * To assess the effect of lanifibranor on liver tests * To assess the effect of lanifibranor on glycaemic parameters * To assess the effect of lanifibranor on lipid parameters * To assess the effect of lanifibranor on liver stiffness and steatosis assessed by elastography. * To assess the effect of lanifibranor on health-related quality of life * To assess the safety of lanifibranor * To assess population PK modeling through plasma levels of lanifibranor using sparse sampling scheme (only for DBPC period)
Interventions
DRUGIVA337
A total of 1000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part A and Part B.
DRUGPlacebo
A total of 1000 patients will be randomised to receive lanifibranor (800 mg/day) or lanifibranor (1200 mg/day), or matching placebo, employing a 1:1:1 randomisation scheme, respectively, without interruption between Part A and Part B.
Sponsors
Inventiva Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Prescreening Criteria: * Diagnosed with NASH on prior liver biopsy * Type 2 diabetes with high waist circumference or obesity or hepatic steatosis on ultrasound * At least 3 of the components of metabolic syndrome Inclusion Criteria: 1. Male or female, aged ≥18 years at the time of signing informed consent 2. Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF): 1. Steatosis score ≥1 2. Activity score: A3 or A4 3. Fibrosis score: F2 or F3 3. No qualitative change in dose for the drugs listed below: 1. Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists) or sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors): for at least 3 months 2. Vitamin E (if at a dose ≥400 IU/day): for at least 6 months 3. Statins: for at least 3 months 4. No qualitative change in dose for all other chronically administered drugs for at least 3 months prior to Screening 5. Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods) 6. 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.
Exclusion criteria
Liver-related: 1. Documented causes of chronic liver disease other than NASH 2. Histologically documented liver cirrhosis (fibrosis stage F4) 3. History or current diagnosis of hepatocellular carcinoma (HCC) 4. History of or planned liver transplant 5. Positive human immunodeficiency virus (HIV) serology 6. ALT or AST \>5 × ULN 7. AST\<0.6 ULN if the liver biopsy has to be performed in the scope of the study 8. Abnormal synthetic liver function as defined by Screening central laboratory evaluation 9. Haemoglobin \<110 g/L (11 g/dL) for females and \<120 g/L (12 g/dL) for males 10. Patient currently receiving any approved treatment for NASH or obesity 11. Current or recent history (\<5 years) of significant alcohol consumption 12. 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: 13. HbA1c \>9% at Screening 14. Diabetes mellitus other than type 2 15. Current treatment with insulin 16. Treatment with PPAR-gamma agonists (thiazolidinediones \[TZDs\]) 12 months before screening or historical biopsy. Obesity related: 17. Bariatric surgery: Restrictive procedures are allowed, if performed \>6 months prior to the qualifying liver biopsy; malabsorptive procedures and procedures combining both restrictive and malabsorptive methods are not allowed within 5 years of the qualifying liver biopsy. Cardiovascular related: 18. History of heart failure with reduced left ventricular ejection fraction (LVEF) 19. Atrial fibrillation requiring anticoagulation 20. Unstable heart failure 21. Uncontrolled hypertension at Screening (values \>160/100 mm Hg) General safety: 22. Women currently breastfeeding 23. Previous exposure to lanifibranor 24. Participation in any clinical trial investigational medicinal product/device within 3 months from Screening or 5 half-lives from Screening, whichever is longer 25. Concomitant treatment with PPAR-alpha agonists (fibrates)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resolution of NASH and improvement of fibrosis | Part A: Date of randomisation until the date of biopsy at Week 72 | Part A: DBPC: 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 |
| Safety Analyses | 48 weeks after completion of DBPC period | Part B: ATE: * Using the DBPC on-treatment period, comparing the 2 active arms versus placebo * Using the DBPC +ATE on treatment periods, assessing the 2 active arms. For adverse events, adjudicated liver events, and DILI and MACE events, in addition to the raw cumulative incidence proportions, the exposure-adjusted incidence rates will be provided based on the time patients are at risk. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czechia, France, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Poland, Portugal, Puerto Rico, South Africa, Spain, Ukraine, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORArun J Sanyal, MD
VCU Health, Gastroenterology Hepatology and Nutrition, 1200 West Broad Street, Richmond VA23298, USA
PRINCIPAL_INVESTIGATORSven Francque, MD
Division of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium
Outcome results
None listed