A Study to Evaluate Seladelpar in Subjects With Nonalcoholic Steatohepatitis (NASH)
Condition: NASH - Nonalcoholic Steatohepatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Seladelpar; Placebos
Intervention description: 10 mg, 20 mg, or 50 mg; Matching placebo Capsule
Intervention MeSH terms: Seladelpar
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomization: 1:2:2:2 (placebo: seladelpar 10 mg: 20 mg: 50 mg)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double Blind Placebo Controlled
Enrollment: 181.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      A Phase 2, Double-Blind (DB), Randomized, Placebo-Controlled Study Followed by an Open-Label
      Extension Period to Evaluate the Activity of Seladelpar in Subjects with Nonalcoholic
      Steatohepatitis (NASH)

      OLE phase was not analyzed due to the early termination of the study
    

Eligibility criteria:

        DB Inclusion Criteria:

          1. Must be able to provide written informed consent (signed and dated) and any
             authorizations required by local law

          2. 18 to 75 years old (inclusive)

          3. Histological evidence of definite NASH on a liver biopsy (obtained during the
             screening period or historical liver biopsy obtained no more than 90 days prior to the
             initial screening visit)

          4. NAS of 4 points or greater with a score of at least 1 point in each component
             (steatosis, lobular inflammation, and ballooning)

          5. Fibrosis stage 1, 2, or 3 on liver biopsy

          6. MRI-PDFF ≥ 10%

          7. Females of reproductive potential must use at least one barrier contraceptive and a
             second effective birth control method during the study and for at least 30 days after
             the last dose of study drug. Male subjects who are sexually active with female
             partners of reproductive potential must use barrier contraception and their female
             partners must use a second effective birth control method during the study and for at
             least 90 days after the last dose of study drug.

        DB Exclusion Criteria:

          1. Significant alcohol consumption, defined as more than 2 drink units per day
             (equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men,
             or inability to reliably quantify alcohol intake

          2. Treatment with drugs associated with nonalcoholic fatty liver disease (NAFLD)
             (amiodarone, methotrexate, oral glucocorticoids at doses greater than 5 mg/day,
             tamoxifen, estrogens at doses greater than those used for hormone replacement or
             contraception, anabolic steroids (such as testosterone and valproic acid) for more
             than 4 weeks within the last 2 months prior to the initial screening

          3. Treatment with pioglitazone or high-dose vitamin E (>400 IU/day) within the last 2
             months prior to the initial screening

          4. Initiation of treatment with a glucagon-like peptide-1 (GLP-1) agonist or a dose
             change within the last 2 months prior to the initial screening

          5. Prior or planned bariatric surgery (a prior reversed sleeve gastrectomy is permitted)

          6. Poorly controlled type 2 diabetes mellitus as defined by hemoglobin A1c [HbA1c] 9.5%
             or higher or type 1 diabetes mellitus

          7. Diabetic patients who are taking sodium/glucose cotransporter 2 (SGLT-2) inhibitors
             must be on a stable dose within 2 months prior to the initial screening and throughout
             the study

          8. Significant weight loss within the last 6 months (e.g., > 10%)

          9. Use of any weight-loss medication for 3 months prior to and during the study period

         10. Body mass index (BMI) < 18.5 kg/m2

         11. Hepatic decompensation defined as the presence of any of the following:

               -  Serum albumin less than 3.5 g/dL

               -  International normalized ratio (INR) greater than 1.4 (unless due to therapeutic
                  anticoagulants)

               -  Total bilirubin greater than 2 mg/dL with the exception of Gilbert syndrome

               -  History of esophageal varices, ascites, or hepatic encephalopathy

         12. Other chronic liver diseases

               -  Active hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)

               -  Active hepatitis C as defined by presence of hepatitis C virus antibody (HCV AB)
                  plus a positive HCV RNA

               -  History or evidence of current active autoimmune hepatitis

               -  History or evidence of primary biliary cholangitis (PBC)

               -  History or evidence of primary sclerosing cholangitis

               -  History or evidence of Wilson's disease

               -  History or evidence of alpha-1-antitrypsin deficiency

               -  History or evidence of hemochromatosis

               -  History or evidence of drug-induced liver disease, as defined exposure and
                  history

               -  Known bile duct obstruction

               -  Suspected or proven liver cancer

         13. ALT > 200 U/L

         14. AST < 20 U/L

         15. Creatine kinase (CK) > upper limit of normal (ULN)

         16. Serum creatinine > ULN

         17. Platelet < lower limit of normal (LLN)

         18. Inability to obtain a liver biopsy

         19. History of biliary diversion

         20. Known history of human immunodeficiency virus (HIV) infection

         21. History of malignancy diagnosed or treated within 2 years

               -  Recent localized treatment of squamous or non-invasive basal cell skin cancers is
                  permitted

               -  Cervical carcinoma in-situ is allowed if appropriately treated prior to Screening

               -  Participants under active evaluation for malignancy are not eligible

         22. Active substance abuse, based on Investigator judgment, including inhaled or injected
             drugs, within 1 year prior to the initial screening

         23. Females who are pregnant or breastfeeding

         24. Patients unable to undergo MRI-PDFF due to:

               -  Contraindication to MRI examination

               -  Severe claustrophobia impacting ability to perform MRI during the study, despite
                  mild sedation/treatment with an anxiolytic

               -  Weight or girth exceeds the scanner capacities

         25. Treatment with any other investigational therapy or device within 30 days or within
             five half-lives, whichever is longer, prior to the initial screening

         26. Active, serious medical disease with likely life expectancy < 5 years

         27. Any other condition(s) that would compromise the safety of the subject or compromise
             study quality as judged by the Investigator

        OLE Phase Enrollment Criteria

        Subjects must fulfill the following before allowing to start OLE dosing:

          1. Provide informed consent on or before Day 1 and prior to any OLE-related study
             procedures.

          2. Completed through the Week 52 biopsy and Week 56 lab assessments in the DB phase

          3. Meet the above DB phase Inclusion and Exclusion Criteria before Day 1 of the OLE
             phase, with the exception of the following:

               -  AST < 20 U/L

               -  Inability to obtain a liver biopsy (no new biopsy required for OLE)

               -  Unable to undergo MRI-PDFF (no imaging performed in OLE)