Non-Alcoholic Steatohepatitis (NASH) and fibrosis MedDRA version: 20.0 Level: PT Classification code 10016642 Term: Fibrosis System Organ Class: 10018065 - General disorders and administration site conditions MedDRA version: 22.0 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: Elafibranor
Product Code: GFT505
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Elafibranor
CAS Number: 824932-88-9
Current Sponsor code: GFT505
Concentration unit: mg milligram
Sponsors
Genfit SA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Males or females aged from 18 to 75 years inclusive at first Screening Visit. 2. Must provide signed written informed consent and agree to comply with the study protocol. 3. Females participating in this study must be of nonchildbearing potential or using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below: o Cessation of menses for at least 12 months due to ovarian failure o Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure o If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient) o Using a highly effective nonhormonal method of contraception (bilateral tubal occlusion, vasectomized partner, or intra-uterine device) o Double contraception with barrier AND highly effective hormonal method of contraception (oral, intravaginal, or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; or intrauterine hormone-releasing system). The hormonal contraception must be started at least 1 month prior to Randomization. 4. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to Screening or during the Screening Period) with at least 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3). 5. NAS =4. 6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. For patients with fibrosis stage 1, only patients at high risk of progression will be included meaning with a NAS =5 and at least 2 of the following conditions: persistent elevated ALT (absence of normal value of ALT within the past year), obesity defined by a BMI = 30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or HOMA-IR >6. 7. Patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have: o 1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy within 6 months before Screening is available) o 1 liver biopsy after 72-weeks of treatment for assessment of the treatment effects on NASH o a final liver biopsy after approximately 4 years of treatment (V13), unless a liver biopsy has already been performed within the past year o 1 liver biopsy performed only in the case of suspicion of cirrhosis (to have a histological confirmation) 8. If a patient is treated with 1 of the following drugs: vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to diagnostic liver biopsy is required. 9. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, change in anti-diabetic therapy must follow these requirements: o no qualitative change 6 months prior to diagnostic liver biopsy up to Randomization (i.e., implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors,
Exclusion criteria
Exclusion criteria: 1. Known chronic heart failure (Grade I to IV of New York Heart Association classification). 2. History of efficient bariatric surgery within 5 years prior to Screening, or planned bariatric surgery in the course of the study. 3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy. 4. Type 1 diabetes patients. 5. Patients with hemoglobin A1c [HbA1c] >9.0%. If abnormal at the first Screening Visit, the HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c (HbA1c >9.0%) leads to exclusion. 6. Patients receiving thiazoledinediones (glitazones [pioglitazone, rosiglitazone]) unless the drug was discontinued at least 6 months before the diagnostic liver biopsy. 7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening such as: stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial infarction, revascularization procedures). 8. Weight loss of more than 5% within 6 months prior to Randomization. 9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded. 10. Current or recent history (12 13. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the recommendations of National Law in force applicable to clinical trials. 14. Patients who cannot be contacted in case of emergency. 15. Known hypersensitivity to the investigation product or any of its formulation excipients. 16. Patients with previous exposure to elafibranor. 17. Patients who are currently participating in, plan to participate in, or have participated in an investigational drug trial or medical device trial containing active substance within 30 days or five half-lives, whichever is longer, prior to Screening. Concomitant medications: 18. Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept constant for at least 2 months prior to Screening. 19. Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: corticosteroids (parenteral & oral chronic administration only), amiodarone (Cordarone), tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objectives - surrogate endpoint To evaluate the efficacy of elafibranor 120 mg QD versus placebo for 72 weeks vs placebo on resolution of NASH without worsening of fibrosis • Resolution of NASH is defined as the disappearance of ballooning and disappearance or persistence of minimal lobular inflammation (grade 0 or 1) with an overall pattern of injury not qualifying for steatohepatitis. • Worsening of fibrosis is evaluated using the NASH Clinical Research Network (CRN) fibrosis staging system and defined as progression of at least 1 stage. Primary objectives - long-term endpoints To evaluate the efficacy of elafibranor 120 mg QD versus placebo on clinical outcomes described as a composite endpoint composed of death due to any cause, histological liver cirrhosis and the full list of portal hypertension/cirrhosis related events (please refer to the protocol for a full list of events).;Secondary Objective: Key secondary objectives (at surrogate endpoint analysis) To assess histological changes after 72 weeks of treatment, at the time of interim analysis, on the following endpoint: • Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring. To assess the clinical benefit after 72 weeks of treatment on the following metabolic endpoints: • Changes from baseline in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) Other secondary objectives • To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the endpoints listed in section 2.3 of the protocol • To assess the endpoints listed in section 2.3 of the protocol at Week 72 and at the end of the LTTP • To assess the onset to events listed in section 2.3 of the protocol;Primary end point(s): Primary endpoint: Surrogate endpoint - resolution of NASH - To evaluate the efficacy of elafibranor 120 mg versus placebo on the resolution of NASH wit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoint (at surrogate endpoint analysis) Percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring at 72 weeks. Changes from baseline to Week 72 in triglycerides, Non-HDL cholesterol, HDL cholesterol, LDL cholesterol, HbA1c (in diabetic patients), HOMA-IR (in non-diabetic patients) Other secondary endpoints • To assess histological changes after 72 weeks of treatment and at the end of the LTTP on the following endpoints: o percentage of patients with resolution of NASH without worsening of fibrosis (at the end of LTTP) o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring (at the end of LTTP) o percentage of patients with improvement of fibrosis of at least 1 stage according to NASH CRN scoring without worsening of NASH o percentage of patients with no worsening of Fibrosis and no worsening of NASH o percentage of patients with resolution of NASH and improvement of Fibrosis o percentage of patients with at least 1 point improvement in histological scores (NASH CRN scoring: NAS [sum of steatosis, hepatic ballooning and lobular inflammation], steatosis, hepatic ballooning, lobular inflammation), fibrosis (NAFLD Ishak scoring system), or portal inflammation o percentage of patients with improvement of NAS of at least 2 points o percentage of patients with improvement of NAS of at least 2 points and with at least 1 point improvement in hepatic ballooning o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to NAS scoring and steatosis-activityfibrosis (SAF) scoring o percentage of patients with at least a 1 point improvement in disease activity score (sum of ballooning and lobular inflammation scores) according to NAS scoring and with at least 1 point improvement in hepatic ballooning o percentage of patients with at least a 1 poi | — |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, Colombia, Czech Republic, Denmark, Finland, France, Germany, Italy, Mexico, Netherlands, Portugal, Romania, Russian Federation, South Africa, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States
Contacts
Public ContactPascal Birman
Genfit SA
Outcome results
None listed