Nonalcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes (T2DM)
Conditions
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.
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.
Interventions
DRUGLanifibranor
The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day
OTHERPlacebo
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.
Sponsors
Inventiva Pharma
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double-blind, placebo-controlled trial.
Intervention model description
A two arm randomized (1:1), double-blind, placebo-controlled, trial.
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
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 * 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. 1. 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). 2. 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). * 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 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. 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: 1. History of myopathies or evidence of active muscle diseases 2. 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% * Significant systemic or major illnesses other than liver disease, including those listed in
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Intrahepatic Triglycerides (IHTG) Quantified by Proton Magnetic Resonance and Spectroscopy (¹H-MRS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With NAFLD Resolution, Defined as Having ≤ 5.5% IHTG (Quantified by 1H- MRS). | 24 weeks of treatment. | Percentage of patients with NAFLD resolution, defined as having ≤ 5.5% IHTG (quantified by 1H- MRS) in both arms. |
| Improvement in Hepatic Insulin Sensitivity (Hepatic Insulin Resistance Index Reported as Relative Percent Change) | 24 weeks of treatment. | 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). |
| Improvement in Adipose Tissue Insulin Sensitivity. | 24 weeks of treatment. | 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. |
| Improvement in Muscle Insulin Sensitivity (Rd). | 24 weeks of treatment. | 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). |
| Absolute Change in Glycemic Control (Hemoglobin A1c). | 24 weeks of treatment. | Absolute changes from baseline will be compared between both arms (i.e., percentage at 24 weeks subtracted from the percentage at baseline). |
| 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 a decrease from baseline in IHTG (quantified by ¹H-MRS) to week 24 of ≥ 30% in each group. |
| Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Vibration Controlled Transient Elastography in kPa) on Imaging. | 24 weeks of treatment. | Changes from baseline in liver stiffness measurement in kPa by vibration controlled transient elastography measured in both arms. |
| Change in Plasma Biomarkers of Liver Fibrosis (Plasma Cytokeratin 18 Measured in IU/L). | 24 weeks of treatment. | Absolute change (Mean ± SD) changes from baseline in plasma cytokeratin 18 (IU/L) levels in both arms. |
| Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography in kPa) on Imaging. | 24 weeks of treatment. | Changes from baseline in liver stiffness measurement by magnetic resonance elastography is measured in both arms (absolute change in kPa from baseline). |
| Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography) on Imaging. | Baseline measurement of liver stiffness by magnetic resonance elastography is reported in each arm. | Baseline liver stiffness measurement (LSM) by magnetic resonance elastography (in kPa) in both arms. |
| Change in Plasma HDL-C (mg/dl). | 24 weeks of treatment. | Changes from baseline will be compared between both arms. |
Countries
United States
Participant flow
Pre-assignment details
Of 128 total enrolled participants, 38 subjects with type 2 diabetes met inclusion criteria and were randomized to be treated. 10 healthy controls met inclusion criteria and completed imaging and other study assessments. This study was performed during the epidemic of COVID that greatly impacted recruitment and promoted dropout.
Participants by arm
| Arm | Count |
|---|---|
| Lanifibranor Arm Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving lanifibranor 800 mg/day.
Lanifibranor: The film-coated tablet contains 400 mg of the active ingredient lanifibranor (IVA337) for an immediate release formulation. Participants receive 800mg/ day | 20 |
| Placebo Two arm, randomized (1:1), double-blind, placebo-controlled, 24-week treatment study receiving placebo.
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. | 18 |
| Healthy Control Group (Not a Treatment Arm) This group ONLY underwent baseline labs, baseline liver fat assessment and one insulin sensitivity measurement to establish the normal for these parameters and to which compare the 2 treatment arms (i.e., lanifibranor and placebo arms). They are NOT treatment arms and participation ended after qualifying and the above studies. | 10 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Lanifibranor Arm | Placebo | Healthy Control Group (Not a Treatment Arm) |
|---|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 8 | 61 years STANDARD_DEVIATION 7 | 58 years STANDARD_DEVIATION 11 | 43 years STANDARD_DEVIATION 18 |
| Intrahepatic triglyceride content | 19.5 % STANDARD_DEVIATION 7.1 | 21 % STANDARD_DEVIATION 7 | 18 % STANDARD_DEVIATION 7 | 3 % STANDARD_DEVIATION 1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 18 Participants | 15 Participants | 9 Participants |
| Region of Enrollment United States | 48 participants | 20 participants | 18 participants | 10 participants |
| Sex: Female, Male Female | 30 Participants | 11 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Male | 18 Participants | 9 Participants | 5 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 18 | 0 / 10 |
| other Total, other adverse events | 18 / 20 | 17 / 18 | 3 / 10 |
| serious Total, serious adverse events | 1 / 20 | 0 / 18 | 0 / 10 |
Outcome results
Primary
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.
Time frame: 24 weeks of treatment
Population: We report absolute change from baseline in LS mean \[95% CI\]
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Change in Intrahepatic Triglycerides (IHTG) Quantified by Proton Magnetic Resonance and Spectroscopy (¹H-MRS) | -8.7 percentage decrease from baseline |
| Placebo | Change in Intrahepatic Triglycerides (IHTG) Quantified by Proton Magnetic Resonance and Spectroscopy (¹H-MRS) | -3.0 percentage decrease from baseline |
Secondary
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).
Time frame: 24 weeks of treatment.
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Absolute Change in Glycemic Control (Hemoglobin A1c). | -0.7 absolute percent change from baseline |
| Placebo | Absolute Change in Glycemic Control (Hemoglobin A1c). | -0.1 absolute percent change from baseline |
Secondary
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.
Time frame: 24 weeks of treatment.
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lanifibranor Arm | Change in Plasma Biomarkers of Liver Fibrosis (Plasma Cytokeratin 18 Measured in IU/L). | -130.71 absolute change in from baseline in IU/L | Standard Deviation 164.28 |
| Placebo | Change in Plasma Biomarkers of Liver Fibrosis (Plasma Cytokeratin 18 Measured in IU/L). | -70.21 absolute change in from baseline in IU/L | Standard Deviation 230.39 |
Secondary
Change in Plasma HDL-C (mg/dl).
Changes from baseline will be compared between both arms.
Time frame: 24 weeks of treatment.
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Change in Plasma HDL-C (mg/dl). | 7.6 absolute change in mg/dl from baseline |
| Placebo | Change in Plasma HDL-C (mg/dl). | 0.9 absolute change in mg/dl from baseline |
Secondary
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).
Time frame: 24 weeks of treatment.
Population: Two subjects in the lanifibranor group missing this measurement due to technical errors
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography in kPa) on Imaging. | 0.23 kPa |
| Placebo | Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography in kPa) on Imaging. | -0.06 kPa |
Secondary
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.
Time frame: 24 weeks of treatment.
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Vibration Controlled Transient Elastography in kPa) on Imaging. | -1.49 absolute change in kPa from baseline |
| Placebo | Changes in Hepatic Fibrosis (Liver Stiffness Measurement by Vibration Controlled Transient Elastography in kPa) on Imaging. | -0.34 absolute change in kPa from baseline |
Secondary
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.
Time frame: Baseline measurement of liver stiffness by magnetic resonance elastography is reported in each arm.
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lanifibranor Arm | Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography) on Imaging. | 2.8 kPa | Standard Deviation 0.8 |
| Placebo | Hepatic Fibrosis (Liver Stiffness Measurement by Magnetic Resonance Elastography) on Imaging. | 2.5 kPa | Standard Deviation 1.1 |
Secondary
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.
Time frame: 24 weeks of treatment.
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Improvement in Adipose Tissue Insulin Sensitivity. | -2.7 index |
| Placebo | Improvement in Adipose Tissue Insulin Sensitivity. | -0.7 index |
Secondary
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).
Time frame: 24 weeks of treatment.
Population: Full Analyses Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Improvement in Hepatic Insulin Sensitivity (Hepatic Insulin Resistance Index Reported as Relative Percent Change) | -26 percentage of baseline value |
| Placebo | Improvement in Hepatic Insulin Sensitivity (Hepatic Insulin Resistance Index Reported as Relative Percent Change) | -7 percentage of baseline value |
Secondary
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).
Time frame: 24 weeks of treatment.
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Lanifibranor Arm | Improvement in Muscle Insulin Sensitivity (Rd). | 30 percentage change from baseline |
| Placebo | Improvement in Muscle Insulin Sensitivity (Rd). | 0 percentage change from baseline |
Secondary
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.
Time frame: 24 weeks of treatment.
Population: ≥30% reduction in IHTG
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanifibranor Arm | Percentage of Patients With a Decrease From Baseline in IHTG (Quantified by ¹H-MRS) to Week 24 of ≥ 30%. | 65 percentage of participants |
| Placebo | Percentage of Patients With a Decrease From Baseline in IHTG (Quantified by ¹H-MRS) to Week 24 of ≥ 30%. | 22 percentage of participants |
Secondary
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.
Time frame: 24 weeks of treatment.
Population: Full Analyses Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanifibranor Arm | Percentage of Patients With NAFLD Resolution, Defined as Having ≤ 5.5% IHTG (Quantified by 1H- MRS). | 25 percentage of participants |
| Placebo | Percentage of Patients With NAFLD Resolution, Defined as Having ≤ 5.5% IHTG (Quantified by 1H- MRS). | 0 percentage of participants |