A Phase 3 Study Evaluating Long-term Efficacy and Safety of Lanifibranor in Adult Patients With (NASH) and Fibrosis 2 (F2)/Fibrosis 3 (F3) Stage of Liver Fibrosis (NATiV3)

• ClinicalTrials.gov Identifier: NCT04849728
• Recruitment Status: Recruiting
• First Posted: April 19, 2021
• Last Update Posted: January 25, 2023
• Sponsor: Inventiva Pharma
• Information provided by (Responsible Party): Inventiva Pharma

Tracking Information

• First Submitted Date: April 16, 2021
• First Posted Date: April 19, 2021
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: August 19, 2021
• Estimated Primary Completion Date: February 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2021)

• Resolution of NASH and improvement of fibrosis [ Time Frame: Part 1: Date of randomisation until the date of biopsy at Week 72 ]
  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
• Time to first clinical outcome event [ Time Frame: Part 2: Date of randomisation until the End of Study (EoS) date approximately 7 years after first patient randomized ]
  Part 2:

  • Histological progression to cirrhosis (defined as histological confirmation of fibrosis score CRN F4)
  • All-cause mortality
  • Liver transplant
  • Model for End-Stage Liver Disease (MELD) score ≥15
  • New onset ascites requiring treatment
  • Overnight hospitalisation due to hepatic decompensation event(s) including:
    • Hepatic encephalopathy Grade ≥2 (as assessed by West Haven scale)
    • Variceal bleeding
    • Spontaneous bacterial peritonitis (assessed by positive culture or cell count)

Original Primary Outcome Measures (submitted: April 16, 2021)

Resolution of NASH [ Time Frame: Date of randomisation until the date of biopsy at Week 72 ]

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

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 3 Study Evaluating Long-term Efficacy and Safety of Lanifibranor in Adult Patients With (NASH) and Fibrosis 2 (F2)/Fibrosis 3 (F3) Stage of Liver Fibrosis
• Official Title: 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
• Brief Summary: This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage 2 or 3

Detailed Description

Primary objectives

This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage 2 or 3 and consists of 2 parts - Part 1 and Part 2, with the following primary objectives:

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 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 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
• To assess the effect of lanifibranor compared to placebo on glycaemic parameters
• To assess the effect of lanifibranor compared to placebo on lipid parameters
• To assess the effect of lanifibranor compared to placebo on liver stiffness
• To assess the effect of lanifibranor compared to placebo on health-related quality of life
• To assess the long-term safety (up to 7 years) of lanifibranor
• To assess population PK modeling of lanifibranor using sparse sampling scheme

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: NASH - Nonalcoholic Steatohepatitis

Intervention

• Drug: IVA337
  A total of 2000 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 1 and Part 2.
  Other Name: Lanifibranor
• Drug: Placebo
  A total of 2000 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 1 and Part 2.

Study Arms

• Experimental: Lanifibranor (IVA 337) (800 mg/day)
  2 Lanifibranor tablets 400mg + 1 Placebo to match tablet with food --> once a day (quaque die, QD)
  Interventions:

  • Drug: IVA337
  • Drug: Placebo
• Experimental: Lanifibranor (IVA 337) (1200 mg/day)
  3 Lanifibranor tablets 400mg with food --> once a day (quaque die, QD)
  Intervention: Drug: IVA337
• Placebo Comparator: Matching placebo
  3 Placebo to match tablets with food --> once a day (quaque die, QD)
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 16, 2021): 2000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2028
• Estimated Primary Completion Date: February 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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. Stable 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): Stable dose for at least 3 months
   2. Vitamin E (if at a dose ≥400 IU/day): Stable dose for at least 6 months
   3. Statins: Stable dose for at least 3 months
4. All other chronically administered drugs must be stable 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. Abnormal synthetic liver function as defined by Screening central laboratory evaluation
8. Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males
9. Patient currently receiving any approved treatment for NASH or obesity
10. Current or recent history (<5 years) of significant alcohol consumption

11. 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:

12. HbA1c >9% at Screening
13. Diabetes mellitus other than type 2
14. Current treatment with insulin

15. Previous or current treatment with PPAR-gamma agonists (thiazolidinediones [TZDs])

    Obesity related:

16. 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:

17. History of heart failure with reduced left ventricular ejection fraction (LVEF)
18. Atrial fibrillation requiring anticoagulation
19. Unstable heart failure

20. Uncontrolled hypertension at Screening (values >160/100 mm Hg)

    General safety:

21. Women currently breastfeeding
22. Previous exposure to lanifibranor
23. Participation in any clinical trial investigational medicinal product/device within 3 months from Screening or 5 half-lives from Screening, whichever is longer
24. Concomitant treatment with PPAR-alpha agonists (fibrates)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pascaline Clerc; 2024998937/0644637545; clinical.contact@inventivapharma.com

• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, France, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Poland, Portugal, Puerto Rico, South Africa, Spain, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04849728
• Other Study ID Numbers: 337HNAS20011
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Inventiva Pharma
• Original Responsible Party: Same as current
• Current Study Sponsor: Inventiva Pharma
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Arun J Sanyal, MD; VCU Health, Gastroenterology Hepatology and Nutrition, 1200 West Broad Street, Richmond VA23298, USA
• Principal Investigator: Sven Francque, MD; Division of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium

• PRS Account: Inventiva Pharma
• Verification Date: January 2023