Nonalcoholic Fatty Liver Disease (NAFLD)Phase 2NCT03459079
Lanifibranor in Patients With Type 2 Diabetes & Nonalcoholic Fatty Liver Disease
A Phase 2 study testing Lanifibranor in people with Nonalcoholic Fatty Liver Disease (NAFLD) and Type 2 Diabetes (T2DM), run by University of Florida at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 21 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Nonalcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes (T2DM)
- What is being tested?
- Lanifibranor
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 128 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Aug 2018to 1 Jun 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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).
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- 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).
- 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.
Who cannot join
- 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).
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- 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.
- Treatment with strong inducers or inhibitors of CYP2C8, or treatment with substrates of CYP2B6 or CYP2C8. When administered chronically, they should be replaced 2 months before trial entry (See Inclusion criterion #3). If not administered chronically, they should be stopped at least 7 days before first dosing.
- -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 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.
- 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.
- 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%
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Efficacy, Safety and Mechanism of Action of Lanifibranor (IVA337) in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
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.
Read the 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.
- Being tested
- Lanifibranor, Placebo
- Medical subject headings
- Non-alcoholic Fatty Liver Disease, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LanifibranorDrug
Also called IVA 337
The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day
PlaceboOther
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.
| Study group | Role | What they receive |
|---|---|---|
| lanifibranor arm | Active comparator | Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving lanifibranor 800 mg/day. Receives: Drug: Lanifibranor |
| Placebo | Placebo comparator | Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving placebo. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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%.
Percentage of patients with a decrease from baseline in IHTG (quantified by ¹H-MRS) to week 24 of ≥ 30% in each group.
Measured: 24 weeks of treatment.
Percentage of Patients With NAFLD Resolution, Defined as Having ≤ 5.5% IHTG (Quantified by 1H- MRS).
Percentage of patients with NAFLD resolution, defined as having ≤ 5.5% IHTG (quantified by 1H- MRS) in both arms.
Measured: 24 weeks of treatment.
Improvement in Hepatic Insulin Sensitivity (Hepatic Insulin Resistance Index Reported as Relative Percent Change)
Changes from baseline in hepatic insulin sensitivity (Hepatic Insulin Resistance Index) as a relative percent change is presented (i.e. [24 week result- baseline result]/baseline result *100).
Measured: 24 weeks of treatment.
Improvement in Adipose Tissue Insulin Sensitivity.
Changes from baseline in absolute value of adipose tissue insulin resistance (ADIPO-IR) index will be compared between both arms. This is calculated using the formula below:
Adipo-IR index = fasting serum free fatty acid concentration x fasting plasma insulin level. A higher value indicated higher insulin resistance.
Measured: 24 weeks of treatment.
Improvement in Muscle Insulin Sensitivity (Rd).
Relative percent changes from baseline in insulin-stimulated muscle glucose disposal (%) will be compared between both arms (i.e. [24 week result- baseline result]/baseline result *100).
Measured: 24 weeks of treatment.
Absolute Change in Glycemic Control (Hemoglobin A1c).
Absolute changes from baseline will be compared between both arms (i.e., percentage at 24 weeks subtracted from the percentage at baseline).
Measured: 24 weeks of treatment.
Change in Plasma HDL-C (mg/dl).
Changes from baseline will be compared between both arms.
Measured: 24 weeks of treatment.
Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Vibration Controlled Transient Elastography in kPa) on Imaging.
Changes from baseline in liver stiffness measurement in kPa by vibration controlled transient elastography measured in both arms.
Measured: 24 weeks of treatment.
Change in Plasma Biomarkers of Liver Fibrosis (Plasma Cytokeratin 18 Measured in IU/L).
Absolute change (Mean ± SD) changes from baseline in plasma cytokeratin 18 (IU/L) levels in both arms.
Measured: 24 weeks of treatment.
Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography in kPa) on Imaging.
Changes from baseline in liver stiffness measurement by magnetic resonance elastography is measured in both arms (absolute change in kPa from baseline).
Measured: 24 weeks of treatment.
Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography) on Imaging.
Baseline liver stiffness measurement (LSM) by magnetic resonance elastography (in kPa) in both arms.
Measured: Baseline measurement of liver stiffness by magnetic resonance elastography is reported in each arm.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2018
- Study start14 Aug 2018
- Primary completion18 Apr 2023
- Study completion1 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Nonalcoholic Fatty Liver Disease (NAFLD)Studies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A two arm randomized (1:1), double-blind, placebo-controlled, trial.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 128 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Collaborators
- Inventiva Pharma
- Responsible party
- Sponsor
- Investigators
- Kenneth Cusi, MD, Principal investigator, University of Florida
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03459079
- Sponsor's protocol ID
- IRB201800838 -A
- Other IDs
- PRO00018845 AGR00010853, OCR17599
- Status last verified
- Sep 2024
- First submitted
- 2 Mar 2018
- Last updated
- 19 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: There is not a plan to make IPD available.
Publications
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.
PubMed 17135584Cusi 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.
PubMed 27322798Cusi 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.
PubMed 22326434Lomonaco 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.
PubMed 26861926Bril 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.
PubMed 28223446Boubia 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.
PubMed 29446942Wettstein 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.
PubMed 29404476Avouac 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.
PubMed 28801346Ruzehaji 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.
PubMed 26961294Barb 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.
PubMed 39824443
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy, Safety and Mechanism of Action of Lanifibranor (IVA337) in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
- ClinicalTrials.gov ID
- NCT03459079
- Acronym / sponsor ID
- IRB201800838 -A
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 128 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Collaborators
- Inventiva Pharma
- Study start
- 14 Aug 2018 (actual)
- Primary completion
- 18 Apr 2023 (actual)
- Study completion
- 1 Jun 2023 (actual)
- First posted
- 8 Mar 2018 (actual)
- Results
- Posted 19 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- A two arm randomized (1:1), double-blind, placebo-controlled, trial.
| Arm | Type | Receives |
|---|---|---|
| lanifibranor arm | Active comparator | Drug: LanifibranorTwo arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving lanifibranor 800 mg/day. |
| Placebo | Placebo comparator | Other: PlaceboTwo arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving placebo. |
Who may qualify
- Ages
- 21 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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.
- Presence of hepatic steatosis (Intrahepatic Triglycerides IHTG) > 10 % determined by Magnetic Resonance and Spectroscopy (1H-MRS).
Key exclusion criteria (29 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LanifibranorAlso: IVA 337The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day | Drug | lanifibranor arm |
| PlaceboFilm-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 | Placebo |
Primary outcome
Change in Intrahepatic Triglycerides (IHTG) Quantified by Proton Magnetic Resonance and Spectroscopy (¹H-MRS)
Time frame: 24 weeks of treatment
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.
11 secondary outcomes
Percentage of Patients With a Decrease From Baseline in IHTG (Quantified by ¹H-MRS) to Week 24 of ≥ 30%.
Time frame: 24 weeks of treatment.
Percentage of Patients With NAFLD Resolution, Defined as Having ≤ 5.5% IHTG (Quantified by 1H- MRS).
Time frame: 24 weeks of treatment.
Improvement in Hepatic Insulin Sensitivity (Hepatic Insulin Resistance Index Reported as Relative Percent Change)
Time frame: 24 weeks of treatment.
Improvement in Adipose Tissue Insulin Sensitivity.
Time frame: 24 weeks of treatment.
Improvement in Muscle Insulin Sensitivity (Rd).
Time frame: 24 weeks of treatment.
Absolute Change in Glycemic Control (Hemoglobin A1c).
Time frame: 24 weeks of treatment.
Change in Plasma HDL-C (mg/dl).
Time frame: 24 weeks of treatment.
Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Vibration Controlled Transient Elastography in kPa) on Imaging.
Time frame: 24 weeks of treatment.
Change in Plasma Biomarkers of Liver Fibrosis (Plasma Cytokeratin 18 Measured in IU/L).
Time frame: 24 weeks of treatment.
Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography in kPa) on Imaging.
Time frame: 24 weeks of treatment.
Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography) on Imaging.
Time frame: Baseline measurement of liver stiffness by magnetic resonance elastography is reported in each arm.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17135584Belfort 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.
- Background: PubMed 27322798Cusi 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.
- Background: PubMed 22326434Cusi 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.
- Background: PubMed 26861926Lomonaco 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.
- Background: PubMed 28223446Bril 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.
- Background: PubMed 29446942Boubia 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.
- Background: PubMed 29404476Wettstein 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.
- Background: PubMed 28801346Avouac 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.
- Background: PubMed 26961294Ruzehaji 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.
- Derived from this study: PubMed 39824443Barb 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.
- Website of the Division of Endocrinology, Diabetes and Metabolism at the University of FloridaLink provided by the sponsor.
- Individual participant dataSharing planned: No. There is not a plan to make IPD available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kenneth Cusi, MD principal investigator
University of Florida
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lanifibranor in people with Nonalcoholic Fatty Liver Disease (NAFLD) and Type 2 Diabetes (T2DM), run by University of Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Intrahepatic Triglycerides (IHTG) Quantified by Proton Magnetic Resonance and Spectroscopy (¹H-MRS) (time frame: 24 weeks of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03459079, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.