Study to Evaluate the Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

Phase 2

Completed

Conditions: Nonalcoholic Steatohepatitis

Interventions: Drug: SEL
Drug: FIR
Drug: CILO
Drug: Placebo to match FIR
Drug: Placebo to match CILO
Drug: Placebo to match SEL

Registration Number: NCT03449446

Lead Sponsor: Gilead Sciences

Brief Summary: The primary objectives of this study are:

* To assess the safety and tolerability of selonsertib (SEL), firsocostat (FIR) and cilofexor (CILO), administered alone or in combination, in participants with bridging fibrosis or compensated cirrhosis due to NASH

* To evaluate changes in liver fibrosis, without worsening of NASH

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 395

Inclusion Criteria

Liver biopsy consistent with NASH and F3 or F4 in the opinion of the central reader
In participants who have never had a liver biopsy, liver stiffness by FibroScan® ≥ 14.0 kPa and Enhanced Liver Fibrosis (ELF™) Test score ≥ 9.8 at Screening
Screening laboratory parameters, as determined by the central laboratory:
- Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft-Gault equation
- Hemoglobin A1c (HbA1c) ≤ 9.5%
- Alanine aminotransferase (ALT) < 5 x Upper Limits of Normal (ULN)
- Platelet count ≥ 125,000/μL

Key

Exclusion Criteria

Prior history of decompensated liver disease including ascites, hepatic encephalopathy, or variceal bleeding
Child-Pugh (CP) score > 6 at Screening, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation
Model for End-Stage Liver Disease (MELD) score > 12 at Screening, unless due to an alternate etiology such as therapeutic anticoagulation
Other causes of liver disease based on medical history and/or centralized review of liver histology, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment
History of liver transplantation
Current or prior history of hepatocellular carcinoma

Note: Other protocol defined Inclusion/ Exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Selonsertib (SEL)	SEL	Participants will receive SEL + placebo to match firsocostat 20 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 48 weeks.
Selonsertib (SEL)	Placebo to match FIR	Participants will receive SEL + placebo to match firsocostat 20 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 48 weeks.
Selonsertib (SEL)	Placebo to match CILO	Participants will receive SEL + placebo to match firsocostat 20 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 48 weeks.
Firsocostat (FIR)	FIR	Participants will receive placebo to match SEL 18 mg tablet + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Firsocostat (FIR)	Placebo to match CILO	Participants will receive placebo to match SEL 18 mg tablet + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Firsocostat (FIR)	Placebo to match SEL	Participants will receive placebo to match SEL 18 mg tablet + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Cilofexor (CILO)	CILO	Participants will receive placebo to match SEL 18 mg tablet + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Cilofexor (CILO)	Placebo to match FIR	Participants will receive placebo to match SEL 18 mg tablet + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Cilofexor (CILO)	Placebo to match SEL	Participants will receive placebo to match SEL 18 mg tablet + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Selonsertib (SEL) + Firsocostat (FIR)	SEL	Participants will receive SEL + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Selonsertib (SEL) + Firsocostat (FIR)	FIR	Participants will receive SEL + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Selonsertib (SEL) + Firsocostat (FIR)	Placebo to match CILO	Participants will receive SEL + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Selonsertib (SEL) + Cilofexor (CILO)	SEL	Participants will receive SEL + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Selonsertib (SEL) + Cilofexor (CILO)	CILO	Participants will receive SEL + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Selonsertib (SEL) + Cilofexor (CILO)	Placebo to match FIR	Participants will receive SEL + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Firsocostat (FIR) + Cilofexor (CILO)	FIR	Participants will receive placebo to match SEL 18 mg tablet + FIR + CILO orally once daily for 48 weeks.
Firsocostat (FIR) + Cilofexor (CILO)	CILO	Participants will receive placebo to match SEL 18 mg tablet + FIR + CILO orally once daily for 48 weeks.
Firsocostat (FIR) + Cilofexor (CILO)	Placebo to match SEL	Participants will receive placebo to match SEL 18 mg tablet + FIR + CILO orally once daily for 48 weeks.
Placebo	Placebo to match FIR	Participants will receive placebo to match SEL 18 mg + placebo to match FIR 20 mg tablet + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Placebo	Placebo to match CILO	Participants will receive placebo to match SEL 18 mg + placebo to match FIR 20 mg tablet + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Placebo	Placebo to match SEL	Participants will receive placebo to match SEL 18 mg + placebo to match FIR 20 mg tablet + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)	First dose date up to 48 weeks plus 30 days
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities	First dose date up to 48 weeks plus 30 days	Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. Participants with any laboratory abnormality were reported.
Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 48	Week 48	Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network classification (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. The 95% CI was based on the Clopper-Pearson method.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (101): The Institute for Liver Health
🇺🇸
Chandler, Arizona, United States
Mayo Clinic Arizona, Mayo Clinic Hospital
🇺🇸
Phoenix, Arizona, United States
Liver Wellness Center
🇺🇸
Little Rock, Arkansas, United States
Arkansas Gastroenterology
🇺🇸
North Little Rock, Arkansas, United States
eStudySite
🇺🇸
Chula Vista, California, United States
Southern California Liver Center
🇺🇸
Coronado, California, United States
Fresno Clinical Research Center
🇺🇸
Fresno, California, United States
UCSD NAFLD Clinical Research Center
🇺🇸
La Jolla, California, United States
Ruane Clinical Research Group Inc.
🇺🇸
Los Angeles, California, United States
Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
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The Institute for Liver Health
🇺🇸Chandler, Arizona, United States