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

  • End date
    Dec 31, 2021
  • participants needed
  • sponsor
    University of Florida
Updated on 13 February 2021
type 2 diabetes mellitus
insulin sensitivity
glomerular filtration rate
liver disease
neutrophil count
fatty liver
conjugated bilirubin
hemoglobin a1c
glycosylated hemoglobin
hepatic fibrosis
sglt2 inhibitor
plasma glucose


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.


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 (H-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 H-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.

Condition NIDDM, Diabetes Mellitus, Diabetes Mellitus, Type 2, Diabetes Prevention, Diabetes Mellitus Types I and II, NAFLD, Non-alcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis (NASH), Nonalcoholic Fatty Liver Disease, Diabetes (Pediatric), Diabetes Mellitus Type 2, Non-alcoholic Fatty Liver Disease, type 2 diabetes mellitus, non-alcoholic fatty liver, type 2 diabetes, type ii diabetes, noninsulin-dependent diabetes mellitus, diabetes type 2
Treatment Placebo, Lanifibranor
Clinical Study IdentifierNCT03459079
SponsorUniversity of Florida
Last Modified on13 February 2021


Yes No Not Sure

Inclusion Criteria

Is your age between 21 yrs and 75 yrs?
Gender: Male or Female
Do you have any of these conditions: Nonalcoholic Steatohepatitis (NASH) or Diabetes Mellitus Types I and II or Diabetes Mellitus, Type 2 or Diabetes Mellitus or Diabetes Mellitus Type 2 ...?
Do you have any of these conditions: Diabetes Mellitus or diabetes type 2 or non-alcoholic fatty liver or Diabetes Mellitus, Type 2 or Diabetes Mellitus Types I and II or type ii diabetes...?
Do you have any of these conditions: non-alcoholic fatty liver or NIDDM or Diabetes Mellitus Type 2 or type ii diabetes or diabetes type 2 or Non-alcoholic Fatty Liver Disease or Nonalcoh...?
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/L
Neutrophil count > 1.5 K/L
Platelets > 100 K/L
Total bilirubin 1.3 mg/dl (22.2 mol/L). Patients with bilirubin 22.2 mol/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, -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
Subjects on sulfonylureas, metformin, DPP-IV, GLP-1RA, unless the dose has been stable for at least 2 months prior to study entry
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
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 mol/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
Lipase > 1.3xULN or >2.0xULN if on a DPP-IV inhibitor or GLP-1RA
Total creatinine kinase > 1.5 X ULN
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
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