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)

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)

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; NASH - Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: IVA337; Drug: Placebo; Drug: Empagliflozin

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Brussels, Belgium, 1070
    • CUB Erasme Hospital
  • Edegem, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen
  • Gent, Belgium, 9000
    • UZ Gent
  • Gent, Belgium, 9000
    • AZ Maria Middelares
• France
  • Angers, France, 49000
    • CHU Angers_Service d'hepatogastro-enterologie
  • Limoges, France, 87042
    • CHU Limoges
  • Paris, France, 75012
    • Hopital Saint Antoine
  • Pessac, France, 33604
    • CHU Bordeaux
  • Toulouse, France, 31059
    • CHU Rangueil
  • Vandoeuvre-lès-Nancy, France, 54500
    • HGE CHRU Nancy
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC
• United Kingdom
  • Hull, United Kingdom, HU32JZ
    • Hull University Teaching Hospital
  • London, United Kingdom, SE59RS
    • King's College Hospital
  • London, United Kingdom, SW17 0QT
    • St Georges Hospital
  • Newcastle upon Tyne, United Kingdom, NE1 7RU
    • Royal Victoria Infirmary
• United States
  • Alabama
    • Homewood, Alabama, United States, 35209
      • Birmingham Digestive Health Research
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Institute for Liver Health DBA Arizona Liver Health
  • Arkansas
    • Conway, Arkansas, United States, 72032
      • ARcare Center for Clinical Research
    • Little Rock, Arkansas, United States, 72205
      • ARcare Center for Clinical Research
  • California
    • Fountain Valley, California, United States, 92708
      • Cure Clinical Research, LLC
    • Gardena, California, United States, 90247
      • Velocity Clinical Research
    • Huntington Park, California, United States, 90255
      • National Research Institute
    • Poway, California, United States, 92064
      • Cadena Care Institute, Llc
  • Florida
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute
    • Lehigh Acres, Florida, United States, 33936
      • Galenus Group
    • Miami, Florida, United States, 33175
      • ProLive Medical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
    • South Bend, Indiana, United States, 46635
      • Digestive Health Research of Southern California
  • Louisiana
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research - New Orleans Area Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Harvard Medical School
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Florham Park, New Jersey, United States, 07932
      • AIG Digestive Disease Research
  • Tennessee
    • Hermitage, Tennessee, United States, 37076
      • Digestive Health Research
  • Texas
    • Austin, Texas, United States, 78745
      • Accelemed Research Institute
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes Research Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation
    • San Antonio, Texas, United States, 78229
      • Diabetes & Glandular Disease Clinic, P.A.
    • Waco, Texas, United States, 76710
      • Impact Research Institute
    • Wichita Falls, Texas, United States, 76301
      • Digestive Health Research of North Texas
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Richmond, Virginia, United States, 23249
      • Central Virginia VA Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lanifibranor (IVA337) (800 mg/day); 2 Lanifibranor tablets 400 mg with food --> once a day (quaque die, QD)	Drug: IVA337; 800 mg; Other Names: Lanifibranor
Placebo Comparator: Matching placebo; 2 Placebo to match tablets with food --> once a day (quaque die, QD)	Drug: Placebo; Placebo to match
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)	Drug: IVA337; 800 mg; Other Names: Lanifibranor; Drug: Empagliflozin; 10 mg; Other Names: Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Absolute change in HbA1c from baseline (Week 0) to Week 24	Date of randomisation until the end of treatment at week 24

Collaborators and Investigators

• Sponsor: Inventiva Pharma

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2022
• Primary Completion (Actual): March 30, 2024
• Study Completion (Actual): June 4, 2024

Study Registration Dates

• First Submitted: January 26, 2022
• First Submitted That Met QC Criteria: February 8, 2022
• First Posted (Actual): February 9, 2022

Study Record Updates

• Last Update Posted (Actual): July 9, 2024
• Last Update Submitted That Met QC Criteria: July 8, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Liver Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 337HNAS21016

Drug and device information, study documents

• 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