Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH)

NCT ID: NCT02781584

Last Updated: 2022-03-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 220 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-13
• Study Completion Date: 2020-12-17

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).

Conditions

Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1: SEL 18 mg (Non-cirrhotic)

Non-cirrhotic participants will receive selonsertib (SEL) 18 mg tablet orally once daily for 12 weeks.

Group Type: EXPERIMENTAL

SEL

Intervention Type: DRUG

Administered orally once daily

Cohort 2: FIR 20 mg (Non-cirrhotic)

Non-cirrhotic participants will receive firsocostat (FIR) 20 mg tablet orally once daily for 12 weeks.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

Cohort 3: CILO 30 mg (Non-cirrhotic)

Non-cirrhotic participants will receive cilofexor (CILO) 30 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

CILO

Intervention Type: DRUG

Administered orally once daily

Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic)

Non-cirrhotic participants will receive SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

SEL

Intervention Type: DRUG

Administered orally once daily

CILO

Intervention Type: DRUG

Administered orally once daily

Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic)

Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

SEL

Intervention Type: DRUG

Administered orally once daily

FIR

Intervention Type: DRUG

Administered orally once daily

Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic)

Non-cirrhotic participants will receive CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

CILO

Intervention Type: DRUG

Administered orally once daily

Cohort 7: CILO 20 mg (Cirrhotic)

Participants with Child-Pugh-Turcotte Class A cirrhosis will receive FIR 20 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

Cohort 8: CILO 30 mg (Cirrhotic)

Participants with Child-Pugh-Turcotte Class A cirrhosis will receive CILO 30 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

CILO

Intervention Type: DRUG

Administered orally once daily

Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic)

Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks.

Group Type: EXPERIMENTAL

SEL

Intervention Type: DRUG

Administered orally once daily

FIR

Intervention Type: DRUG

Administered orally once daily

CILO

Intervention Type: DRUG

Administered orally once daily

Cohort 10: FIR 20 mg + FENO 48 mg

Participants will receive fenofibrate (FENO) 48 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 48 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

FENO

Intervention Type: DRUG

Administered orally once daily

Cohort 11: FIR 20 mg + FENO 145 mg

Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 145 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

FENO

Intervention Type: DRUG

Administered orally once daily

Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g

Participants will receive Vascepa® (VAS) 2 g capsule orally twice daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + VAS 2 g capsule twice daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

CILO

Intervention Type: DRUG

Administered orally once daily

VAS

Intervention Type: DRUG

Administered orally two times daily

Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg

Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + FENO 145 mg tablet orally once daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Group Type: EXPERIMENTAL

FIR

Intervention Type: DRUG

Administered orally once daily

CILO

Intervention Type: DRUG

Administered orally once daily

FENO

Intervention Type: DRUG

Administered orally once daily

Interventions

SEL

Administered orally once daily

Intervention Type: DRUG

FIR

Administered orally once daily

Intervention Type: DRUG

CILO

Administered orally once daily

Intervention Type: DRUG

FENO

Administered orally once daily

Intervention Type: DRUG

VAS

Administered orally two times daily

Intervention Type: DRUG

Other Intervention Names

GS-4997; GS-0976; GS-9674

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gilead Study Director

Role: STUDY_DIRECTOR

Gilead Sciences

Locations

Arizona Liver Health

Chandler, Arizona, United States

Altman Clinical and Translational Research Clinic

La Jolla, California, United States

Ruane Clinical Research Group Inc.

Los Angeles, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

Stanford Hospital and Clinics (SHC)

Stanford, California, United States

Florida Research Institute

Lakewood Rch, Florida, United States

Delta Research Partners, LLC

Bastrop, Louisiana, United States

Gastro One

Germantown, Tennessee, United States

Quality Medical Research

Nashville, Tennessee, United States

Pinnacle Clinical Research, PLLC

Live Oak, Texas, United States

American Research Corporation at the Texas Liver Institute

San Antonio, Texas, United States

Pinnacle Clinical Research, PLLC

San Antonio, Texas, United States

Auckland Clinical Studies Ltd

Auckland, , New Zealand

Countries

United States; New Zealand

References

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

PMID: 29705265 (View on PubMed)

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

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.

Reference Type: RESULT

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.

Reference Type: DERIVED

PMID: 34999207 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: Cohort 1-9 SAP

View Document

Document Type: Statistical Analysis Plan: Cohort 10-11 SAP

View Document

Document Type: Statistical Analysis Plan: Cohort 12-13 SAP

View Document

Other Identifiers

GS-US-384-3914

Identifier Type: -

Identifier Source: org_study_id