Type 2 Diabetes (T2DM) with Non-Alcoholic Steatohepatitis (NASH) MedDRA version: 24.1 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Sponsors
Inventiva S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For an eligible patient, all inclusion criteria must be answered “yes” at Screening and re-confirmed at Baseline (i.e., before randomization). Laboratory tests taken during the screening period will be used to determine eligibility. If information cannot be confirmed in the medical record, responses will be obtained in a patient interview: 1. Able to understand the nature of the study, willing and able to comply with the study procedures and restrictions, and willing to provide informed consent obtained before any study-related activities 2. The patient is willing to continue on the study in case of moving or relocating to a different region/city where there would be no active study site 3. Able to communicate meaningfully with the Investigator and legally competent to provide written informed consent 4. Male or female, aged = 18 years at the time of signing informed consent 5. Diagnosis of NASH a. based on a historical (within 12 months prior to Screening) liver biopsy with a non-alcoholic fatty liver disease activity score (NAS) = 4 with a score of one or more in each sub-component (steatosis, hepatocyte ballooning, lobular inflammation) and no documented cirrhosis in the last 12 months prior to Screening OR b. high-risk NASH defined as cT1 > 875 ms assessed by LiverMultiScan® at Screening 6. HbA1c at screening = 7.0 and = 10.0%, on diet alone, or on metformin (= 1,000 mg/day), and/or dipeptidyl peptidase 4 inhibitor (DPP-IVi) therapy. Doses have to be stable for 3 months prior to informed consent. These medicines will be continued at stable doses during the entire study. 7. Negative pregnancy test at Screening for females of childbearing potential or at least two-year post-menopausal. Women of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile) have to use a highly effective method of contraception throughout the study and for one month after treatment discontinuation. Highly effective contraceptive methods are defined as follows: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (provided he is her sole sexual partner and he has received medical assessment of the surgical success), and true sexual abstinence (when this is in line with the preferred and usual lifestyle of the patient) whereas periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 63 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 16
Exclusion criteria
Exclusion criteria: Liver-related: 1. Documented causes of chronic liver disease other than NASH 2. Histologically documented liver cirrhosis (fibrosis stage F4); or diagnosis of cirrhosis at Screening 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) at Screening 7. Abnormal liver function as defined by central laboratory evaluation of any of the following: a. Albumin 2 × ULN 12. Patient currently receiving any approved treatment for NASH or obesity 13. Current or recent history ( 45 kg/m2 at Screening 21. Weight change > 5% in the 3 months prior to Screening 22. 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 23. Participation in an organized weight loss program in the past 6 months prior to Screening or planned participation through Week 24 Cardiovascular related: 24. History of (within 3 months prior to Screening) or current unstable cardiac dysrhythmias 25. NT-proBNP > 900 pg/mL 26. Unstable heart failure 27. Any other clinically significant cardiovascular event requiring hospitalization within 6 months before Screening 28. Uncontrolled hypertension at Screening (systolic blood pressure [SBP] > 160 mmHg and/or diastolic blood pressure [DBP] > 100 mmHg 29. Stroke or transient ischemic attack within 6 months prior to Screening General safety: 30. Significant systemic or major illnesses other than liver disease that would preclude treatment with lanifibranor and/or empagliflozin 31. Any condition which might jeopardize a patient’s safety or compliance with the protocol, or warrants exclusion from the study 32. Cancer: Presence or history of malignancy within 5 years prior to Screening and/or active neoplasm at Screening. 33. History of bladder disease and/or persistent hematuria within 6 months prior to Screening or current hematuria unless due to a urinary tract infection 34. Renal impairment measured as eGFR 1.5 x ULN 36
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objective To assess the effect of lanifibranor alone compared to placebo and the effect of lanifibranor in combination with empagliflozin compared to placebo on HbA1c after a 24-week treatment duration. Secondary objectives To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24-week treatment duration on: •Liver tests •Markers of glycemic control and insulin resistance •Inflammatory markers •Lipid parameters •Body weight and body composition and To assess the safety and tolerability of lanifibranor alone and in combination with empagliflozin during the 24-week treatment period and the 4-week follow-up period. ;Secondary Objective: Secondary objectives To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24-week treatment duration on: Liver tests, Markers of glycemic control and insulin resistance, Inflammatory markers, Lipid parameters , Body weight and body composition and To assess the safety and tolerability of lanifibranor alone and in combination with empagliflozin during the 24-week treatment period and the 4-week follow-up period. Exploratory objectives : To assess the effect of lanifibranor alone compared to placebo and lanifibranor in combination with empagliflozin compared to placebo after a 24-week treatment duration on: Hepatic fat content ; Steatosis, inflammation and fibrosis ; NASH and fibrosis non-invasive biomarkers; Liver elasticity and tissue attenuation; Liver stiffness; The time to initiation of a rescue medication. To perform population pharmacokinetic (popPK) modelling of lanifibranor ;Primary end point(s): Primary efficacy endpoint •Absolute change in HbA1c from baseline (Week 0) to Week 24 ;Timepoint(s) of evaluation of this end point: Change from baseline (Week 0) to Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints The following endpoints will be evaluated at Week 24: • Change from baseline to Week 24 in liver tests (alanine aminotransferase [ALT], AST, gamma-glutamyl transferase (GGT), alkaline phosphatase [ALP], total and direct bilirubin) • Change from baseline to Week 24 in markers of glycemic control and insulin resistance (determination of hepatic insulin sensitivity, Homeostatic Model Assessment for insulin resistance [HOMA-IR], fasting insulin, fasting plasma glucose [FPG], fructosamine, adiponectin) • Binary endpoint defined as reaching HbA1c 80 ms at Week 24 • Binary endpoints defined as reaching cT1 = 800 ms, and cT1 = 875 ms at Week 24 • Changes from baseline to Week 24 in non-invasive biomarkers related to NASH and fibrosis (included but not limited to: TIMP-1, hyaluronic acid, P3NP, cytokeratin CK18M30 and M65, proC3) • Changes from baseline to Week 24 in VelacurTM ultrasound measures of liver elasticity (kPa) and attenuation (dB/m) (only applies to sites where VelacurTM is available) • Changes from baseline to Week 24 in FibroScan® measures of LSM (kPa), CAP (dB/m) and FAST score (only applies to sites where FibroScan® is available) • Time from randomization to initiation of a rescue medication (weeks) Pharmacokinetic (PK) endpoints • PopPK modelling of trough plasma levels of lanifibranor and its metabolites using a sparse sampling scheme (PK parameters include Cmax, Tmax, AUC, T1/2, CL/F, Vd/F) ;Timepoint(s) of evaluation of this end point: Change from baseline (Week 0) to Week 24 (and intothe 4-week follow-up period specfically for safety and tolerability ) | — |
Countries
France, Netherlands, United Kingdom, United States
Contacts
Public ContactSanjaykumar.PATEL
Inventiva S.A.
Outcome results
None listed