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

NCT03459079 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: IRB201800838 -APRO00018845 AGR00010853OCR17599
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 1

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.

Conditions

Nonalcoholic Fatty Liver Disease (NAFLD); Type 2 Diabetes (T2DM)

Outcome Measures

Primary Outcomes (1)

• Change in Intrahepatic Triglycerides (IHTG) Quantified by Proton Magnetic Resonance and Spectroscopy (¹H-MRS)

  Changes from baseline (Adjusted LS means) in absolute percent for change in intrahepatic triglycerides (IHTG) quantified by proton magnetic resonance and spectroscopy (¹H-MRS)are reported in each arms.

  24 weeks of treatment

Secondary Outcomes (11)

• Percentage of Patients With a Decrease From Baseline in IHTG (Quantified by ¹H-MRS) to Week 24 of ≥ 30%.

  24 weeks of treatment.

• Percentage of Patients With NAFLD Resolution, Defined as Having ≤ 5.5% IHTG (Quantified by 1H- MRS).

  24 weeks of treatment.

• Improvement in Hepatic Insulin Sensitivity (Hepatic Insulin Resistance Index Reported as Relative Percent Change)

  24 weeks of treatment.

• Improvement in Adipose Tissue Insulin Sensitivity.

  24 weeks of treatment.

• Improvement in Muscle Insulin Sensitivity (Rd).

  24 weeks of treatment.

Study Arms (2)

lanifibranor arm

ACTIVE COMPARATOR

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

Drug: Lanifibranor

Placebo

PLACEBO COMPARATOR

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

Other: Placebo

Interventions

Lanifibranor DRUG

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

Also known as: IVA 337

lanifibranor arm

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Subjects should be on stable standard of care and background therapy for ongoing chronic conditions, including stable doses of anti-diabetic medications, for at least two (2) months prior to trial entry
• 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 or GLP1RA. These medicines will be continued at stable doses during the entire study.
• Subjects with an HbA1c \> 8.0% but ≤ 9.5% will have their metformin (minimum dose required: 1,000 mg/day) maximized to 1,000 mg BID and/or glimepiride 2 mg once daily added during the first 2 weeks of the run-in period. The baseline visit to initiate lanifibranor (V4; Time 0 or randomization visit) will be not sooner than 8 weeks from diabetes medication titration and the patient should have an HbA1c ≤9.0% to proceed to randomization (V4).
• In addition, if both metformin and glimepiride (or another sulfonylurea) are already maximized at study entry (or the patient is intolerant to either) and the HbA1c ≥ 9.0% but ≤9.5%, we will add sitagliptin 100 mg daily (or an equivalent dose of another DPP-IV inhibitor) to reach an HbA1c ≤9.0% to proceed to randomization (V4).
• Presence of hepatic steatosis (Intrahepatic Triglycerides IHTG) \> 10 % determined by Magnetic Resonance and Spectroscopy (1H-MRS).
• Have no new symptoms associated with decompensated diabetes in the previous 3 months.
• 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
• Total bilirubin ≤ 1.3 mg/dL (≤ 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.
• Albumin \> 36 g/L
• No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, HCV, Wilson's, α-1-antitrypsin deficiency, hemochromatosis, other).

You may not qualify if:

• Evidence of liver disease other than NAFLD.
• 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 3 months prior to enrollment, 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, GLP-1RA or DPP-IV unless the dose and body weight (within 5%) have been stable for at least two (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:
• i. 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 ii. History of (within prior 3 months) or current unstable cardiac dysrhythmias iii. Uncontrolled hypertension (systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 100 mmHg.
• iv. Stroke or transient ischemic attack within the prior 6 months c. History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer d. History of bladder disease and/or hematuria or has current hematuria unless due to a urinary tract infection e. Any of the following laboratory values: ii. 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.
• iii. Serum ALT \> 3X ULN iv. INR \> 1.2 v. Platelets \< 150,000 per microliter of blood vi. Renal impairment as demonstrated by estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73m2 vii. Total creatinine kinase \> 1.5 X ULN viii. Lipase \> 1.3X ULN or \>2.0X ULN if on a DPP-IV inhibitor. \*(if abnormal values are confirmed when repeated within 3 weeks) ix. Hemoglobin A1c \> 9.5%
• 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.

Sponsors & Collaborators

• University of Florida: lead
• Inventiva Pharma: collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (10)

• Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006 Nov 30;355(22):2297-307. doi: 10.1056/NEJMoa060326.

  PMID: 17135584 BACKGROUND

• Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016 Sep 6;165(5):305-15. doi: 10.7326/M15-1774. Epub 2016 Jun 21.

  PMID: 27322798 BACKGROUND

• Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012 Apr;142(4):711-725.e6. doi: 10.1053/j.gastro.2012.02.003. Epub 2012 Feb 8.

  PMID: 22326434 BACKGROUND

• Lomonaco R, Bril F, Portillo-Sanchez P, Ortiz-Lopez C, Orsak B, Biernacki D, Lo M, Suman A, Weber MH, Cusi K. Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes. Diabetes Care. 2016 Apr;39(4):632-8. doi: 10.2337/dc15-1876. Epub 2016 Feb 9.

  PMID: 26861926 BACKGROUND

• Bril F, Cusi K. Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action. Diabetes Care. 2017 Mar;40(3):419-430. doi: 10.2337/dc16-1787.

  PMID: 28223446 BACKGROUND

• Boubia B, Poupardin O, Barth M, Binet J, Peralba P, Mounier L, Jacquier E, Gauthier E, Lepais V, Chatar M, Ferry S, Thourigny A, Guillier F, Llacer J, Amaudrut J, Dodey P, Lacombe O, Masson P, Montalbetti C, Wettstein G, Luccarini JM, Legendre C, Junien JL, Broqua P. Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) alpha/gamma/delta Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate. J Med Chem. 2018 Mar 22;61(6):2246-2265. doi: 10.1021/acs.jmedchem.7b01285. Epub 2018 Feb 27.

  PMID: 29446942 BACKGROUND

• Wettstein G, Luccarini JM, Poekes L, Faye P, Kupkowski F, Adarbes V, Defrene E, Estivalet C, Gawronski X, Jantzen I, Philippot A, Tessier J, Tuyaa-Boustugue P, Oakley F, Mann DA, Leclercq I, Francque S, Konstantinova I, Broqua P, Junien JL. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol Commun. 2017 Jun 19;1(6):524-537. doi: 10.1002/hep4.1057. eCollection 2017 Aug.

  PMID: 29404476 BACKGROUND

• Avouac J, Konstantinova I, Guignabert C, Pezet S, Sadoine J, Guilbert T, Cauvet A, Tu L, Luccarini JM, Junien JL, Broqua P, Allanore Y. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. Ann Rheum Dis. 2017 Nov;76(11):1931-1940. doi: 10.1136/annrheumdis-2016-210821. Epub 2017 Aug 11.

  PMID: 28801346 BACKGROUND

• Ruzehaji N, Frantz C, Ponsoye M, Avouac J, Pezet S, Guilbert T, Luccarini JM, Broqua P, Junien JL, Allanore Y. Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. Ann Rheum Dis. 2016 Dec;75(12):2175-2183. doi: 10.1136/annrheumdis-2015-208029. Epub 2016 Mar 9.

  PMID: 26961294 BACKGROUND

• Barb D, Kalavalapalli S, Godinez Leiva E, Bril F, Huot-Marchand P, Dzen L, Rosenberg JT, Junien JL, Broqua P, Rocha AO, Lomonaco R, Abitbol JL, Cooreman MP, Cusi K. Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD. J Hepatol. 2025 Jun;82(6):979-991. doi: 10.1016/j.jhep.2024.12.045. Epub 2025 Jan 15.

  PMID: 39824443 DERIVED

Related Links

• Website of the Division of Endocrinology, Diabetes and Metabolism at the University of Florida

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2

Interventions

lanifibranor

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Limitations and Caveats

The original number of patients to be recruited was reduced during the trial based on the results of the NATIVE study (Francque et al, N Engl J Med. 2021 Oct 21;385(17):1547-1558. doi: 10.1056/NEJMoa2036205), as explained in the study protocol.

Results Point of Contact

• Title: Kenneth Cusi
• Organization: University of Florida

kcusi@ufl.edu

352-505-9060

Study Officials

• Kenneth Cusi, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blind, placebo-controlled trial.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: March 2, 2018
• First Posted: March 8, 2018
• Study Start: August 14, 2018
• Primary Completion: April 18, 2023
• Study Completion: June 1, 2023
• Last Updated: September 19, 2024
• Results First Posted: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)