A Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 ) (NATiV3)

• ClinicalTrials.gov Identifier: NCT04849728
• Recruitment Status: Recruiting
• First Posted: April 19, 2021
• Last Update Posted: May 12, 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: May 12, 2023
• Actual Study Start Date: August 19, 2021
• Estimated Primary Completion Date: September 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 30, 2023)

• Resolution of NASH and improvement of fibrosis [ Time Frame: 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 [ Time Frame: 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.

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 Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 )
• Official Title: A Randomised, Double-blind, Placebo-controlled, Multicentre, Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) and Fibrosis Stages F2 and F3
• 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)

• 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 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.
  Other Name: Lanifibranor
• Drug: Placebo
  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.

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: March 30, 2023): 1000
• Original Estimated Enrollment (submitted: April 16, 2021): 2000
• Estimated Study Completion Date: September 30, 2026
• Estimated Primary Completion Date: September 30, 2025 (Final data collection date for primary outcome measure)

Eligibility 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)

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: May 2023