Lanifibranor in Patients With Type 2 Diabetes & Nonalcoholic Fatty Liver Disease

Sponsor

University of Florida (Other)

Overall Status

Recruiting

CT.gov ID

NCT03459079

Collaborator

Inventiva Pharma (Industry)

Enrollment

Location

Arms

43.6

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Nonalcoholic Fatty Liver Disease (NAFLD) Type 2 Diabetes (T2DM)	Drug: Lanifibranor Other: Placebo	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

44 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

A two arm randomized (1:1), double-blind, placebo-controlled, trial.A two arm randomized (1:1), double-blind, placebo-controlled, trial.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

double-blind, placebo-controlled trial.

Primary Purpose:

Treatment

Official Title:

Efficacy, Safety and Mechanism of Action of Lanifibranor (IVA337) in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Actual Study Start Date :

Aug 14, 2018

Anticipated Primary Completion Date :

Apr 1, 2022

Anticipated Study Completion Date :

Apr 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: lanifibranor arm Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving lanifibranor 800 mg/day.	Drug: Lanifibranor The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day Other Names: IVA 337
Placebo Comparator: Placebo Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving placebo.	Other: Placebo 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.

Arm

Intervention/Treatment

Active Comparator: lanifibranor arm

Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving lanifibranor 800 mg/day.

Drug: Lanifibranor

The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day

Other Names:

IVA 337

Placebo Comparator: Placebo

Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving placebo.

Other: Placebo

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.

Outcome Measures

Primary Outcome Measures

Change in intrahepatic triglycerides (IHTG) quantified by proton magnetic resonance and spectroscopy (¹H-MRS) [24 weeks of treatment]
Changes from baseline will be compared between both arms.

Secondary Outcome Measures

Proportion of patients with a decrease from baseline in IHTG (quantified by ¹H-MRS) to week 24 of ≥ 30%. [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Proportion of patients with NAFLD resolution, defined as having ≤ 5.5% IHTG (quantified by 1H- MRS). [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Improvement in hepatic insulin sensitivity and de novo lipogenesis. [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Improvement in adipose tissue insulin sensitivity. [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Improvement in muscle insulin sensitivity (Rd). [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Change in glycemic control (HbA1c). [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Change in plasma lipid profile. [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Changes in hepatic fibrosis on imaging. [24 weeks of treatment.]
Changes from baseline will be compared between both arms.
Change in plasma biomarkers of liver fibrosis. [24 weeks of treatment.]
Changes from baseline will be compared between both arms.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Be able to communicate meaningfully with the investigator and legally competent to provide written informed consent
Have an age between 21 to 75 years inclusive.
Have uncontrolled diabetes with a fasting plasma glucose (FPG) ≥ 100 mg/dL but ≤ 250 mg/dL and HbA1c ≥ 6.0% but ≤ 9.5%, on diet alone, or on metformin (≥1,000 mg/day), and/or sulfonylurea and/or DPP-IV therapy, SGLT2 inhibitors and/or GLP-1RA. These medicines will be continued at stable doses during the entire study.
Presence of hepatic steatosis (Intrahepatic Triglycerides IHTG) ≥ 10 % determined by Nuclear Magnetic Resonance Techniques.
Have no new symptoms associated with decompensated diabetes in the previous 3 months.
Have been on a stable dose of allowed chronic medications for two months prior to entering the double-blind treatment period.
Compensated liver disease with the following hematologic and biochemical criteria on entry into protocol:

Hemoglobin > 11 g/dL for females and > 12 g/dL for males
White blood cell (WBC) > 2.5 K/µL
Neutrophil count > 1.5 K/µL
Platelets > 100 K/µL
Total bilirubin ≤1.3 mg/dl (22.2 µmol/L). Patients with bilirubin ≥22.2 µmol/L can be included if non-conjugated bilirubin in the setting of a Gilbert's syndrome.
Albumin > 36 g/L
Serum creatinine < 1.3 mg/dL (males) or < 1.1 mg/dL (females) or estimated glomerular filtration rate ≥ 60 mL/min/1.73m2

No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, HCV, Wilson's, α-1-antitrypsin deficiency, hemochromatosis, other).
Negative pregnancy test or at least two-year post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progesterone containing) hormonal/ progesterone-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study.

Exclusion Criteria:

Evidence of another form of liver disease.
History of excessive alcohol intake, defined by ≥ 21 units of alcohol per week in males and ≥14 units of alcohol per week in females for two years prior to enrollment, where a "unit" of alcohol is equivalent to 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor.
Unstable metabolic condition: Weight change > 5 kg in the last three months, diabetes with poor glycemic control (HgbA1c > 9.5% or FPG > 250 mg/dl), introduction of an anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening.
History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.
Subjects on sulfonylureas, metformin, DPP-IV, GLP-1RA, unless the dose has been stable for at least 2 months prior to study entry.
Patients on insulin, pioglitazone (or prior use in the past 12 months)
Patients on any of the following medications unless the patient has been on stable doses of such agents for the past two (2) months before entry into the study: thiazide or furosemide diuretics, beta- blockers, or other chronic medications with known adverse effects on glucose tolerance levels. Patients may be taking stable doses of estrogens or other hormonal replacement therapy if the patient has been on these agents for the prior two (2) months. Patients taking systemic glucocorticoids will be excluded.
Patients with history of myopathies or evidence of active muscle diseases
Unstable cardiovascular disease, including unstable angina (i.e., new or worsening symptoms of coronary heart disease within the past 3 months), acute coronary syndrome within the past 6 months, acute myocardial infarction in the past 3 months or heart failure of New York Heart Association class (III-IV) or worsening congestive heart failure, or coronary artery intervention, within the past 6 months
History of (within prior 3 months) or current unstable cardiac dysrhythmias
Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg.
Stroke or transient ischemic attack within the prior 6 months
History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer
History of bladder disease and/or hematuria or has current hematuria unless due to a urinary tract infection
Any of the following laboratory values:
Serum bilirubin > 1.3 mg/dL (or > 22.2 µmol/L). Patients with bilirubin > 1.3 mg/dL can be included if non-conjugated bilirubin in the setting of a Gilbert's syndrome.
Serum ALT > 3X ULN
INR > 1.2
Platelets < 150,000 per microliter of blood.
Renal impairment as demonstrated by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2
Total creatinine kinase > 1.5 X ULN
Lipase > 1.3xULN or >2.0xULN if on a DPP-IV inhibitor or GLP-1RA.
Hemoglobin A1c > 9.5%
Significant systemic or major illnesses other than liver disease, including those listed in exclusion criteria #8 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.
HB antigen > 0, HCV > 0 (patients with a history of HCV infection can be included if HCV PCR is negative since more than 3 years), prior history of HIV infection.
Pregnancy/lactation or inability to adhere to adequate contraception in women of child-bearing potential.
Any other condition which, in the opinion of the investigator would impede competence or compliance or possibly hinder completion of the study.
Body mass index (BMI) > 45 kg/m2.
Type 1 diabetes and type 2 diabetic patient on insulin.
Diabetic ketoacidosis.
Fasting plasma triglycerides > 500 mg/dL.
Hemostasis disorders or current treatment with anticoagulants.
Participation in any other investigational drug study within the previous 3 months.
Have a known hypersensitivity to any of the ingredients or excipients of the IMP including: Lactose monohydrate, hypromellose, sodium lauryl sulphate, sodium starch glycolate, magnesium stearate, Opadry™ II 85F18422, DSS Granular, cellulose microcrystalline, maize starch.
Be possibly dependent on the Investigator (e.g., including, but not limited to, affiliated employee).
Osteopenia or any other well documented bone disease. Patient without well documented osteopenia treated with vitamin D and/or calcium based supplements for preventive reasons can be included.
Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation is permitted at discretion of investigator.
Metallic implant of any sort that prevents MRI examination including, but not limited to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural stimulator, metallic contraceptive device, tattoo, body piercing that cannot be removed, cochlear implant; or any other contraindication to MRI examination..