Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH)
Condition: Nonalcoholic Steatohepatitis (NASH) With Fibrosis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Fibrosis
Intervention: Elafibranor; Placebo
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2157.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Elafibranor; NASH; Nonalcoholic steatohepatitis; Fatty liver disease; Fibrosis

Summary:

      The primary objectives of this study are to evaluate the effect of Elafibranor treatment
      compared to placebo on 1) histological improvement and 2) all-cause mortality and
      liver-related outcomes in patients with nonalcoholic steatohepatitis (NASH) and fibrosis.
    

Eligibility 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:

               1. Cessation of menses for at least 12 months due to ovarian failure,

               2. Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically
                  documented ovarian failure

               3. 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)

               4. Using a highly effective nonhormonal method of contraception (bilateral tubal
                  occlusion, vasectomized partner, or intra-uterine device)

               5. 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 randomization or
             during the screening period) with at least 1 in each component of the NAS score
             (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation
             scored 0-3).

          5. NAS score ≥4.

          6. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging
             system.

          7. Stable dose of vitamin E, polyunsaturated fatty acids, or ursodeoxycholic acid from at
             least 6 months prior to diagnostic liver biopsy

          8. For participants with type 2 diabetes, glycemia must be controlled. If glycemia is
             controlled by antidiabetic drugs, change in anti-diabetic therapy must follow these
             requirements:

               1. No qualitative change 6 months prior to diagnostic liver biopsy up to
                  Randomization (i.e., implementation of a new anti-diabetic therapy) for
                  participants treated with metformin, gliptins, sulfonylureas, sodium/glucose
                  cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or
                  insulin. Dose changes of these medications are allowed in the 6 months prior to
                  diagnostic liver biopsy, except for GLP-1 agonists, which must remain on stable
                  dose in the 6 months prior to diagnostic liver biopsy.

               2. No implementation of GLP-1 agonists and SGLT2 inhibitors up to 72 weeks of
                  treatment (Visit 7).

        Initiation of any other antidiabetic drugs is allowed after Randomization based on treating
        physicians' judgment, except for glitazones which are prohibited 6 months prior to
        diagnostic liver biopsy until the end of treatment.

        Exclusion Criteria:

          1. Known heart failure (Grade I to IV of New York Heart Association classification).

          2. History of efficient bariatric surgery within 5 years prior to screening.

          3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive
             therapy

          4. Type 1 diabetes participants .

          5. Participants with decompensated diabetes (HbA1c>9%).

          6. Participants with a history of clinically significant acute cardiac event within 6
             months prior to screening

          7. Weight loss of more than 5% within 6 months prior to randomization

          8. Compensated and decompensated cirrhosis

          9. Current or recent history (<5 years) of significant alcohol consumption

         10. Pregnant or lactating females or females planning to become pregnant during the study
             period.

         11. Other well documented causes of chronic liver disease according to standard diagnostic
             procedures

         12. Participants with previous exposure to Elafibranor

         13. Prohibited concomitant medication

         14. Any medical conditions that may diminish life expectancy to less than 2 years
             including known cancers.

         15. Evidence of any other unstable or untreated clinically significant immunological,
             endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric
             disease.

         16. Mental instability or incompetence, such that the validity of informed consent or
             ability to be compliant with the study is uncertain.

         17. Participants with biological criteria exclusion as per effective protocol