Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH)
Condition: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD)
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: SEL; FIR; CILO; FENO; VAS
Intervention description: Administered orally once daily; Administered orally once daily; Administered orally once daily; Administered orally once daily; Administered orally two times daily
Intervention MeSH terms: Firsocostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Cohorts 1-6 and 9 will be enrolled sequentially while Cohorts 7 and 8 will be randomized in parallel. Cohorts 10 and 11 will be randomized in parallel. Cohorts 12 and 13 will be randomized in parallel.
Masking: None (Open Label)
Enrollment: 220.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The primary objective of this study is to evaluate the safety and tolerability of
      selonsertib, firsocostat, cilofexor, fenofibrate and/or Vascepa® in adults with nonalcoholic
      fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Males and females between 18-75 years of age (Cohorts 1-9: 18-75 years and Cohorts
             10-13: ≥ 18 years); inclusive based on the date of the screening visit

          -  Willing and able to provide informed consent prior to any study specific procedures
             being performed

          -  For Cohorts 1 through 6 and 9, individuals must meet the following conditions:

               -  Clinical diagnosis of nonalcoholic fatty liver disease (NAFLD)

               -  Screening FibroTest® < 0.75, unless a historical liver biopsy within 12 months of
                  Screening does not reveal cirrhosis. In individuals with Gilbert's syndrome or
                  hemolysis, FibroTest® will be calculated using direct bilirubin instead of total
                  bilirubin,

               -  Screening magnetic resonance imaging - proton density fat fraction (MRI-PDFF)
                  with ≥ 10% steatosis,

               -  Screening magnetic resonance elastography (MRE) with liver stiffness ≥ 2.88 kPa,
                  OR

               -  A historical liver biopsy within 12 months of Screening consistent with NASH
                  (defined as the presence of steatosis, inflammation, and ballooning) with stage
                  2-3 fibrosis according to the NASH Clinical Research Network (CRN) classification
                  (or equivalent), AND

               -  No documented weight loss > 5% between the date of the liver biopsy and
                  Screening;

          -  For Cohorts 7 and 8, individuals must have a clinical diagnosis of NAFLD and have at
             least one of the following criteria:

               -  Screening MRE with liver stiffness ≥ 4.67 kPa,

               -  A historical FibroScan® ≥ 14 kPa within 6 months of Screening,

               -  Screening FibroTest® ≥ 0.75,

               -  A historical liver biopsy consistent with stage 4 fibrosis according to the NASH
                  CRN classification (or equivalent);

          -  For Cohorts 10 and 11, individuals must have a clinical diagnosis of NAFLD and meet at
             least two criteria for metabolic syndrome modified from the NCEP ATP III Guidelines
             and one of the following criteria at Screening:

               -  A historical liver biopsy within 6 months of Screening consistent with NASH and
                  bridging fibrosis (F3) or within 12 months of Screening consistent with NASH and
                  compensated cirrhosis (F4) in the opinion of the investigator,

               -  Screening liver stiffness by MRE ≥ 3.64 kPa;

               -  Screening liver stiffness by FibroScan® ≥ 9.9 kPa;

          -  For Cohorts 12 and 13, individuals must have a clinical diagnosis of NAFLD/NASH and at
             least two criteria for metabolic syndrome as modified from the NCEPT ATP III
             Guidelines, OR one of the following criteria:

               -  A historical liver biopsy within 6 months of Screening consistent with NASH for
                  individuals without compensated cirrhosis (F4); or within 12 months of Screening
                  consistent with NASH for individuals with compensated cirrhosis (F4) in the
                  opinion of the investigator,

               -  A historical MRE with liver stiffness ≥ 2.88 kPa within 6 months of Screening,

               -  A historical FibroScan® with liver stiffness ≥ 9.9 kPa within 6 months of
                  Screening, AND

               -  No documented weight loss > 5% between the date of the historical liver biopsy,
                  historical MRE, or historical FibroScan® and Screening;

          -  Platelet count ≥ 100,000/µL;

          -  Serum creatinine < 2 mg/dL (Cohorts 1-9) at Screening;

          -  Estimated glomerular filtration rate (eGFR) ≥ 80 mL/min (Cohorts 10-11) or ≥ 60 mL/min
             (Cohorts 12-13), as calculated by the Cockcroft-Gault equation at Screening;

          -  For Cohorts 10-13, serum triglyceride level ≥ 150 mg/dL at Screening.

        Key Exclusion Criteria:

          -  Pregnant or lactating females

          -  Other causes of liver disease including autoimmune, viral, and alcoholic liver disease

          -  Any history of decompensated liver disease, including ascites, hepatic encephalopathy
             or variceal bleeding

          -  For Cohorts 7-8, 10-13, Child-Pugh-Turcotte (CPT) score > 6

          -  History of liver transplantation

          -  History of hepatocellular carcinoma;

          -  Weight reduction surgery in the past 2 years or planned during the study;

          -  Documented weight loss > 5% between the date of the historical liver biopsy and
             Screening, if applicable;

          -  Body Mass Index (BMI) < 18 kg/m2;

          -  ALT > 5 x ULN at Screening;

          -  For Cohorts 10-13, HbA1c ≥ 9.5% (or serum fructosamine ≥ 381 µmol if HbA1c is unable
             to be resulted) at Screening;

          -  For Cohorts 10-13, hemoglobin ≤ 10.6 g/dL at Screening;

          -  INR > 1.2 (Cohorts 1-9) or INR > 1.4 (Cohorts 10-13) at Screening, unless on
             anticoagulation therapy;

          -  Total bilirubin > 1x ULN (Cohorts 1 through 6 and 9), >1.5 x ULN (Cohorts 7 and 8), or
             >1.3 x ULN (Cohorts 10-13) except in confirmed cases of Gilbert's syndrome;

          -  Triglycerides ≥ 500 mg/dL (Cohorts 5-8 and 10-13) or ≥ 250 mg/dL (Cohort 9) at
             Screening;

          -  Model for End-Stage Liver Disease (MELD) score > 12 at Screening (Cohorts 10 -13),
             unless due to an alternate etiology such as therapeutic anticoagulation;

          -  Chronic hepatitis B (HBsAg positive);

          -  Chronic hepatitis C (HCV RNA positive). individuals cured of HCV infection less than 2
             years prior to the Screening visit are not eligible (Cohorts 10-13);

          -  HIV Ab positive;

          -  Presence of gallstones within 6 months of Screening (Cohorts 10-13);

          -  Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females
             (1oz/30 mL of alcohol is present in 1 12oz/360 mL beer, 1 4oz/120 mL glass of wine,
             and a 1 oz/30 mL measure of 40% proof alcohol);

          -  Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at
             Screening. Individuals on stable methadone or buprenorphine maintenance treatment for
             at least 6 months prior to Screening may be included in the study. Individuals with a
             positive urine drug screen due to prescription opioid-based medication are eligible if
             the prescription and diagnosis are reviewed and approved by the investigator;

          -  Unstable cardiovascular disease;

          -  History of intestinal resection of the extent that would result in malabsorption;

          -  Use of any prohibited concomitant medications as described in the protocol;

          -  History of a malignancy within 5 years of Screening with the following exceptions:

               -  Adequately treated carcinoma in situ of the cervix,

               -  Adequately treated basal or squamous cell cancer or other localized non-melanoma
                  skin cancer.

        Note: Other protocol defined Inclusion/Exclusion criteria may apply.