NASH - Nonalcoholic Steatohepatitis, Diabetes Mellitus, Type 2
Conditions
Brief summary
The study in the T2DM population is intended to confirm the lanifibranor effect versus placebo on glycemic control and assess a positive effect of the combination of lanifibranor with an SGLT2 inhibitor on glycemic control.
Interventions
Sponsors
Inventiva Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged ≥ 18 years at the time of signing informed consent 2. Diagnosis of NASH, based on histology or cT1≥875ms assessed by LiverMultiScan or cT1≥825ms assessed by LiverMultiScan and hepatic fat content ≥ 10% assessed by MRI-PDFF at screening 3. HbA1c at screening ≥ 7.0 and ≤ 10.0%, on diet alone, or on metformin and/or dipeptidyl peptidase 4 inhibitor (DPP-IVi) therapy. Both with doses to be stable for 3 months 4. Negative pregnancy test at Screening for females of childbearing potential or at least two-year post-menopausal.
Exclusion criteria
Liver-related: 1. Documented causes of chronic liver disease other than NASH 2. Histologically documented liver cirrhosis (fibrosis stage F4) 3. History or current diagnosis of hepatocellular carcinoma (HCC) 4. History of or planned liver transplant 5. Documented history of human immunodeficiency virus (HIV) infection 6. ALT or AST \> 5 × upper limit of normal (ULN) 7. Abnormal liver function as defined by central laboratory evaluation: Albumin \< LLN INR ≥ 1.3 (unless patient is on anticoagulants) Total bilirubin level ≥ 1.5 mg/dL (25.7 µmol/L) (patients with a documented history of Gilbert's syndrome can be enrolled if direct bilirubin is ≤ 0.45 mg/dL (7.7 μmol/L) ) 8. Hemoglobin \< 110 g/L (11 g/dL) for females and \< 120 g/L (12 g/dL) for males 9. WBC \< LLN. A lower count is acceptable in patients with benign ethnic neutropenia, if considered to be clinical insignificant by the investigator 10. Platelet count \< 140,000/µL 11. ALP \> 2 × ULN 12. Patient currently receiving any approved treatment for NASH or obesity 13. Current or recent history (\< 5 years) of significant alcohol consumption 14. Administration of drugs known to produce hepatic steatosis in the 6 months prior to Screening. Diabetes related: 15. Diabetes mellitus other than type 2 16. Diabetic ketoacidosis at Screening 17. Current treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA), insulin or sulfonylurea or treatment within the last 3 months prior to Screening 18. Patients on pioglitazone in the last 12 months prior to Screening. 19. Patients on metformin, DPP-IVi, thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels, unless on stable doses in last 3 months Obesity related: 20. BMI\>45 kg/m2 at screening 21. Introduction of an anti-obesity drug or restrictive bariatric surgery in the past 12 months prior to Screening or planned bariatric surgery through Week 24. Cardiovascular related: 21\. History of or current unstable cardiac dysrhythmias 22. Unstable heart failure 23. Uncontrolled hypertension 24. Stroke or transient ischemic attack General safety: 25\. Significant systemic or major illnesses other than liver disease 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 26. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value \< 60 mL/min 27. Concomitant treatment with PPAR-⍺ agonists (fibrates) 28. Patients on Vitamin E at doses ≥ 400 IU/day; doses of ≥ 400 IU/day are allowed when no qualitative change in dose for 6 months prior to Screening 29. Have a known hypersensitivity to any of the IMPs 30. Previous exposure to lanifibranor or empagliflozin 31. Present pregnancy/lactation 32. Metallic implant of any sort that prevents MRI examination 33. Participation in any clinical trial of an approved or non approved investigational medicinal product/device within 3 months from Screening or five half-lives of the investigational drug from Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in HbA1c | From Baseline to Week 24 | Effect of lanifibranor alone compared to placebo and the effect of lanifibranor in combination with empagliflozin compared to placebo on absolute change in HbA1c from baseline (Week 0) to Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Tests (ALT) | from Baseline to Week 24 | Defined as Absolute Change from Baseline |
| Change in Liver Tests (AST) | from Baseline to Week 24 | Defined as Absolute Change from Baseline |
| Percentage Change in Insulin Resistance and Glycaemic Control (HOMA-IR) | from Baseline to Week 24 | HOMA-IR : The homeostatic model assessment for insulin resistance (HOMA-IR) is a method used to quantify insulin resistance, and was derived by the central laboratory from glucose and insulin values using the formula (Fasting glucose mg/dL x fasting insulin µIU/mL) / 405. Lower values are considered better outcome. |
| Change in Insulin Resistance and Glycaemic Control (Insulin) | from Baseline to Week 24 | Defined as Relative Change from Baseline |
| Change in Insulin Resistance and Glycaemic Control (Adiponectin) | from Baseline to Week 24 | Defined as Fold Change from Baseline |
| Change in Lipid Parameters (HDL Cholesterol) | from Baseline to Week 24 | Defined as Relative Change |
| Change in Body Weight and Body Composition (Body Weight) | from Baseline to Week 24 | Defined as Relative Change from Baseline |
| Change in Body Weight and Body Composition (VAT/SAT Ratio) | from Baseline to Week 24 | Ratio VAT / SAT - Results for Relative Change from Baseline VAT : MRI L3 visceral adipose tissue SAT : MRI L3 subcutaneous adipose tissue |
Countries
Belgium, France, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
Recruitment of patients started in June 2022 and last patient was recruited in November 2023. A total of 213 patients were screened for the study.
Pre-assignment details
Patients were invited to participate by their referent doctor based on their medical records. They had to fulfil all eligibility criteria. Main reason for non-randomization was screen failure. 39 patients were treated and included in the Full Analysis Set (FAS). Enrollment, disposition and analyses are based on the FAS (n=39).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 54.6 years STANDARD_DEVIATION 12.38 |
| BMI | 37.62 kg/m2 STANDARD_DEVIATION 4.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HbA1c <7.5% | 5 Participants |
| HbA1c ≥7.5% | 8 Participants |
| Height | 167.08 cm STANDARD_DEVIATION 9.418 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 103.30 Kg STANDARD_DEVIATION 12.437 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 | 0 / 14 |
| other Total, other adverse events | 10 / 12 | 9 / 13 | 8 / 14 |
| serious Total, serious adverse events | 0 / 12 | 1 / 13 | 0 / 14 |
Outcome results
None listed