Placebo-controlled, Proof-of-concept Study to Evaluate the Safety and Efficacy of Lanifibranor Alone and in Combination With SGLT2 Inhibitor EmpaGliflozin in patiEnts With NASH and Type 2 Diabetes Mellitus (LEGEND)

• ClinicalTrials.gov Identifier: NCT05232071
• Recruitment Status: Active, not recruiting
• First Posted: February 9, 2022
• Last Update Posted: February 23, 2024
• Sponsor: Inventiva Pharma
• Information provided by (Responsible Party): Inventiva Pharma

Tracking Information

• First Submitted Date: January 26, 2022
• First Posted Date: February 9, 2022
• Last Update Posted Date: February 23, 2024
• Actual Study Start Date: June 29, 2022
• Estimated Primary Completion Date: March 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 14, 2022)

Assessment of the effect of lanifibranor alone compared to placebo and the effect of lanifibranor in combination with empagliflozin compared to placebo on absolute change in HbA1c from baseline (Week 0) to Week 24 [ Time Frame: Date of randomisation until the end of treatment at week 24 ]

Absolute change in HbA1c from baseline (Week 0) to Week 24

Original Primary Outcome Measures (submitted: February 8, 2022)

Assessment of the effect of lanifibranor alone compared to placebo and the effect of lanifibranor in combination with empagliflozin compared to placebo on HbA1c [ Time Frame: Date of randomisation until the end of treatment at week 24 ]

Absolute change in HbA1c from baseline (Week 0) to Week 24

• 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: Placebo-controlled, Proof-of-concept Study to Evaluate the Safety and Efficacy of Lanifibranor Alone and in Combination With SGLT2 Inhibitor EmpaGliflozin in patiEnts With NASH and Type 2 Diabetes Mellitus
• Official Title: A Placebo-controlled, Proof-of-concept Study to Evaluate the Safety and Efficacy of Lanifibranor Alone and in Combination With the Sodium-glucose Transport Protein 2 (SGLT2) Inhibitor EmpaGliflozin in patiEnts With Non-alcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM)
• Brief Summary: The study in the T2DM population is intended to confirm the lanifibranor effect versus placebo on glycemic control and assess a positive effect of the combination of lanifibranor with an SGLT2 inhibitor on glycemic control.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• NASH - Nonalcoholic Steatohepatitis
• Diabetes Mellitus, Type 2

Intervention

• Drug: IVA337
  800 mg
  Other Name: Lanifibranor
• Drug: Placebo
  Placebo to match
• Drug: Empagliflozin
  10 mg
  Other Name: Jardiance

Study Arms

• Experimental: Lanifibranor (IVA337) (800 mg/day)
  2 Lanifibranor tablets 400 mg with food --> once a day (quaque die, QD)
  Intervention: Drug: IVA337
• Placebo Comparator: Matching placebo
  2 Placebo to match tablets with food --> once a day (quaque die, QD)
  Intervention: Drug: Placebo
• Experimental: Lanifibranor (IVA337) (800 mg/day) plus Empagliflozin (10mg/day)
  2 Lanifibranor tablets 400 mg plus 1 Empagliflozin tablet 10mg with food --> once a day (quaque die, QD)
  Interventions:

  • Drug: IVA337
  • Drug: Empagliflozin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 22, 2024): 42
• Original Estimated Enrollment (submitted: February 8, 2022): 63
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: March 30, 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. Diagnosis of NASH, based on histology or cT1≥875ms assessed by LiverMultiScan or cT1≥825ms assessed by LiverMultiScan and hepatic fat content ≥ 10% assessed by MRI-PDFF at screening
3. HbA1c at screening ≥ 7.0 and ≤ 10.0%, on diet alone, or on metformin and/or dipeptidyl peptidase 4 inhibitor (DPP-IVi) therapy. Both with doses to be stable for 3 months
4. Negative pregnancy test at Screening for females of childbearing potential or at least two-year post-menopausal.

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. Documented history of human immunodeficiency virus (HIV) infection
6. ALT or AST > 5 × upper limit of normal (ULN)

7. Abnormal liver function as defined by central laboratory evaluation:

   Albumin < LLN INR ≥ 1.3 (unless patient is on anticoagulants) Total bilirubin level ≥ 1.5 mg/dL (25.7 µmol/L) (patients with a documented history of Gilbert's syndrome can be enrolled if direct bilirubin is ≤ 0.45 mg/dL (7.7 μmol/L) )

8. Hemoglobin < 110 g/L (11 g/dL) for females and < 120 g/L (12 g/dL) for males
9. WBC < LLN. A lower count is acceptable in patients with benign ethnic neutropenia, if considered to be clinical insignificant by the investigator
10. Platelet count < 140,000/µL
11. ALP > 2 × ULN
12. Patient currently receiving any approved treatment for NASH or obesity
13. Current or recent history (< 5 years) of significant alcohol consumption

14. Administration of drugs known to produce hepatic steatosis in the 6 months prior to Screening.

    Diabetes related:

15. Diabetes mellitus other than type 2
16. Diabetic ketoacidosis at Screening
17. Current treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA), insulin or sulfonylurea or treatment within the last 3 months prior to Screening
18. Patients on pioglitazone in the last 12 months prior to Screening.

19. Patients on metformin, DPP-IVi, thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels, unless on stable doses in last 3 months

    Obesity related:

20. BMI>45 kg/m2 at screening
21. Introduction of an anti-obesity drug or restrictive bariatric surgery in the past 12 months prior to Screening or planned bariatric surgery through Week 24.

Cardiovascular related:

21. History of or current unstable cardiac dysrhythmias 22. Unstable heart failure 23. Uncontrolled hypertension 24. Stroke or transient ischemic attack

General safety:

25. Significant systemic or major illnesses other than liver disease and pulmonary disease, organ transplantation, serious psychiatric disease, that, in the opinion of the investigator, would preclude treatment with lanifibranor and/or adequate follow up 26. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value < 60 mL/min 27. Concomitant treatment with PPAR-⍺ agonists (fibrates) 28. Patients on Vitamin E at doses ≥ 400 IU/day; doses of ≥ 400 IU/day are allowed when no qualitative change in dose for 6 months prior to Screening 29. Have a known hypersensitivity to any of the IMPs 30. Previous exposure to lanifibranor or empagliflozin 31. Present pregnancy/lactation 32. Metallic implant of any sort that prevents MRI examination 33. Participation in any clinical trial of an approved or non approved investigational medicinal product/device within 3 months from Screening or five half-lives of the investigational drug from Screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Netherlands, United Kingdom, United States

Administrative Information

• NCT Number: NCT05232071
• Other Study ID Numbers: 337HNAS21016
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: 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: Not Provided
• PRS Account: Inventiva Pharma
• Verification Date: February 2024