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)

Study Overview
=================
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

Official Title
-----------------
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib, GS-0976, GS-9674, and Combinations in Subjects With Bridging (F3) Fibrosis or Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

Conditions
-----------------
Nonalcoholic Steatohepatitis

Intervention / Treatment
-----------------
* Drug: SEL
* Drug: FIR
* Drug: CILO
* Drug: Placebo to match FIR
* Drug: Placebo to match CILO
* Drug: Placebo to match SEL


Participation Criteria
=================
Eligibility Criteria
-----------------
Key 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selonsertib (SEL)<br>Participants will receive SEL + placebo to match firsocostat 20 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 48 weeks. | Drug: SEL<br>* 18 mg tablet administered orally once daily without regard to food<br>Drug: Placebo to match FIR<br>* Tablet administered orally once daily without regard to food<br>Drug: Placebo to match CILO<br>* Tablet administered orally once daily without regard to food<br>|
| Experimental: Firsocostat (FIR)<br>Participants will receive placebo to match SEL 18 mg tablet + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks. | Drug: FIR<br>* 20 mg tablet administered orally once daily without regard to food<br>* Other names: GS-0976;Drug: Placebo to match CILO<br>* Tablet administered orally once daily without regard to food<br>Drug: Placebo to match SEL<br>* Tablet administered orally once daily without regard to food<br>|
| Experimental: Cilofexor (CILO)<br>Participants will receive placebo to match SEL 18 mg tablet + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks. | Drug: CILO<br>* 30 mg tablet administered orally once daily without regard to food<br>* Other names: GS-9674;Drug: Placebo to match FIR<br>* Tablet administered orally once daily without regard to food<br>Drug: Placebo to match SEL<br>* Tablet administered orally once daily without regard to food<br>|
| Experimental: Selonsertib (SEL) + Firsocostat (FIR)<br>Participants will receive SEL + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks. | Drug: SEL<br>* 18 mg tablet administered orally once daily without regard to food<br>Drug: FIR<br>* 20 mg tablet administered orally once daily without regard to food<br>* Other names: GS-0976;Drug: Placebo to match CILO<br>* Tablet administered orally once daily without regard to food<br>|
| Experimental: Selonsertib (SEL) + Cilofexor (CILO)<br>Participants will receive SEL + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks. | Drug: SEL<br>* 18 mg tablet administered orally once daily without regard to food<br>Drug: CILO<br>* 30 mg tablet administered orally once daily without regard to food<br>* Other names: GS-9674;Drug: Placebo to match FIR<br>* Tablet administered orally once daily without regard to food<br>|
| Experimental: Firsocostat (FIR) + Cilofexor (CILO)<br>Participants will receive placebo to match SEL 18 mg tablet + FIR + CILO orally once daily for 48 weeks. | Drug: FIR<br>* 20 mg tablet administered orally once daily without regard to food<br>* Other names: GS-0976;Drug: CILO<br>* 30 mg tablet administered orally once daily without regard to food<br>* Other names: GS-9674;Drug: Placebo to match SEL<br>* Tablet administered orally once daily without regard to food<br>|
| Experimental: Placebo<br>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. | Drug: Placebo to match FIR<br>* Tablet administered orally once daily without regard to food<br>Drug: Placebo to match CILO<br>* Tablet administered orally once daily without regard to food<br>Drug: Placebo to match SEL<br>* Tablet administered orally once daily without regard to food<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. Participants with any laboratory abnormality were reported. | First dose date up to 48 weeks plus 30 days | 
| Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at 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. | Week 48 |