Clinical trial NCT02781584: Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH)
Official title: A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic Fatty Liver Disease (NAFLD)
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2016-05-24
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
timeFrame: Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
measure: Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events
timeFrame: Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
measure: Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities
timeFrame: Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
Secondary outcomes:
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Arizona Liver Health
state: Arizona
city: La Jolla
country: United States
facility: Altman Clinical and Translational Research Clinic
state: California
city: Los Angeles
country: United States
facility: Ruane Clinical Research Group Inc.
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics (SHC)
state: California
city: Lakewood Ranch
country: United States
facility: Florida Research Institute
state: Florida
city: Bastrop
country: United States
facility: Delta Research Partners, LLC
state: Louisiana
city: Germantown
country: United States
facility: Gastro One
state: Tennessee
city: Nashville
country: United States
facility: Quality Medical Research
state: Tennessee
city: Live Oak
country: United States
facility: Pinnacle Clinical Research, PLLC
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at the Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research, PLLC
state: Texas
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies Ltd
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Lawitz E, Neff G, Ruane P, Ziad Y, Jia C, Chuang J, et al. Fenofibrate Mitigates Increases in Serum Triglycerides Due to the ACC Inhibitor Firsocostat in Patients with Advanced Fibrosis Due to NASH. Poster presented at: The American Association for the Study of Liver Diseases (AASLD): The Liver Meeting; November 8-12, 2019; Boston, MA.
citation: Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, Tarrant JM, Nguyen T, Han L, Chung C, Ray AS, McHutchison JG, Subramanian GM, Myers RP, Middleton MS, Sirlin C, Loomba R, Nyangau E, Fitch M, Li K, Hellerstein M. Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2018 Dec;16(12):1983-1991.e3. doi: 10.1016/j.cgh.2018.04.042. Epub 2018 Apr 26.
citation: Lawitz E, Herring R, Younes ZH, Gane E, Ruane P, Schall RA, et al. Proof of Concept Study of an Apoptosis-Signal Regulating Kinase (ASK1) Inhibitor (Selonsertib) in Combination With An Acetyl-CoA Carboxylase Inhibitor (GS-0976) or a Farnesoid X Receptor Agonist (GS-9674) in Nash [Abstract PS-105]. European Association for the Study of the Liver (EASL); 2018 11-15 April; Paris, France.
citation: Lawitz E, Li K, Tarrant JM, Vimal M, Xu R, Song Q, et al. Hepatic de Novo Lipogenesis is Elevated in Patients with NASH Independent of Disease Severity [Abstract 2217]. American Association for the Study of Liver Diseases (AASLD); 2017 20-24 October Washington, DC.
citation: Lawitz EJ, Poordad F, Coste A, Loo N, Djedjos CS, McColgan B, et al. Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to suppression of hepatic de novo lipogenesis and significant improvements in MRI-PDFF, MRE, and markers of fibrosis after 12 weeks of therapy in patients with NASH [Abstract GS-009]. The International Liver Congress™ 2017: European Association for the Study of the Liver (EASL); 2017 19-23 April; Amsterdam, the Netherlands.
citation: Lawitz E, Bhandari BR, Ruane P, Kohli A, Harting E, Jia C, et al. Fenofibrate is Safe and Mitigates Increases in Serum Triglycerides in NASH Patients Treated with the Combination of the ACC Inhibitor Firsocostat and the FXR Agonist Cilofexor: A Randomized Trial. Poster presented at: The European Association for the Study of the Liver (EASL): International Liver Congress; June 23-26, 2021; Virtual Meeting.
citation: Lawitz EJ, Bhandari BR, Ruane PJ, Kohli A, Harting E, Ding D, Chuang JC, Huss RS, Chung C, Myers RP, Loomba R. Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat. Clin Gastroenterol Hepatol. 2023 Jan;21(1):143-152.e3. doi: 10.1016/j.cgh.2021.12.044. Epub 2022 Jan 6.