Lanifibranor in Patients With Type 2 Diabetes & Nonalcoholic Fatty Liver Disease
Condition: Nonalcoholic Fatty Liver Disease (NAFLD); Type 2 Diabetes (T2DM)
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

Summary: 
      The primary aim is to establish the safety, efficacy and mechanism of action of lanifibranor
      in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD).
      Specifically, to determine if lanifibranor decreases intrahepatic triglycerides (IHTG)
      (primary endpoint), improves hepatic insulin sensitivity, endogenous (hepatic) glucose
      production, de novo lipogenesis (DNL), HbA1c and lipid profiles. In addition, exploratory
      analysis with surrogate plasma biomarkers and imaging on liver fibrosis changes on with
      treatment will be performed.
    

Detailed description: 
      The study is a two-arm (placebo, lanifibranor 800 mg/day), randomized (1:1), double-blind,
      placebo-controlled, 24-week treatment study. Thirty four (n=34)patients with T2DM will be
      randomized, allowing for a 10% drop-out rate. The diagnosis of NAFLD on imaging will be done
      by measuring IHTG using the gold-standard magnetic resonance and spectroscopy (¹H-MRS)
      technique. Ten non-diabetic subjects without NAFLD will also serve as a control group for the
      metabolic and imaging procedures. The study will last 34-36 weeks (~6-8 weeks for run-in, 24
      weeks of treatment and 4 weeks post-study follow-up), with an estimated recruitment period of
      ~9 months. Patients with uncontrolled T2DM and a diagnosis of "fatty liver" per history
      (elevated AST/ALT and/or liver fat on liver ultrasound or ¹H-MRS and/or other appropriate
      imaging technique - see below). Participants may be treated by diet only, or be on a stable
      dose of metformin and/or a sulfonylurea and/or a DPP-IV inhibitor for ≥ 2 months prior to
      enrollment. If the HbA1c is ≤8.0% on any of these diabetes medications, the dose of these
      medications will be kept stable throughout the study and baseline studies performed as
      outlined below. If the HbA1c is > 8.0% but ≤ 9.5%, metformin (minimum dose required: 1,000
      mg/day for metformin) and/or a sulfonylurea (minimum dose required: glimepiride 2 mg once
      daily) will be added, or doses maximized, during the first 2 weeks of the lead-in period.
      Afterwards, patient's metformin or sulfonylurea dose will be maintained at the new dose
      stable for 4 weeks before baseline metabolic and study-specific liver imaging.

      After patients sign the informed consent and meet eligibility criteria, baseline imaging and
      metabolic studies will be performed. These will include measurement of IHTG by 1H-MRS, liver
      fibrosis by VCTE (Fibroscan) and MRE, and additional imaging by T1 MRI mapping. Metabolic
      testing will be done with the patient being admitted to the CRC (clinical research unit) for
      an overnight stay. Assessment of insulin sensitivity and DNL will be done with the
      administration of stable isotopes of glucose (intravenously) and deuterium labeled water
      (orally) to measure glucose and lipid turnover and substrate oxidation (with indirect
      calorimetry) during a euglycemic hyperinsulinemic clamp.

      After all baseline tests are completed, patients will be asked to take a therapeutic dose of
      800 mg lanifibranor (QD), or placebo, for 24 weeks. They will be closely followed by study
      staff every 4 weeks with visits to the CRC and interim phone calls. At 24 weeks, all baseline
      tests will be repeated and treatment considered completed. There will be a final, off-drug,
      safety follow-up visit 4 weeks after treatment at week 28. After this the participant will
      have completed all study procedures.

      Note: The investigators recalculated the sample size for the primary endpoint of change in
      intrahepatic triglyceride (IHTG) measured by 1H-MRS with lanifibranor (800 mg/day) vs.
      placebo based on the data from the population with diabetes from the Phase IIb NATIVE
      (NCT03008070: NAsh Trial to Validate IVA337 Efficacy; liver histology results) and comparing
      to prior studies by Dr. Cusi et al that had simultaneous liver histology and liver fat
      measured by 1H-MRS (Belfort et al, NEJM 2006; Cusi et al, Annals Int Med 2016). From this
      analysis, the required sample size per group calls for 15 patients in each arm (lanifibranor
      vs. placebo) to complete treatment. Conservatively assuming that 10 % of the randomized
      patients will not complete the trial (dropouts), the total number of patients to be
      randomized is 33-34 patients.
    

Intervention name(s): Lanifibranor; Placebo
Intervention type(s): Drug; Other
Intervention description(s): The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day; Film-coated tablets with a core containing 900 mg of a physical mixture of lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate serve as placebo.
Other intervention name(s): IVA 337
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A two arm randomized (1:1), double-blind, placebo-controlled, trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment