Safety and Efficacy of Selonsertib in Adults With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce associated complications in adults with cirrhosis due to NASH.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: SEL
* Drug: Placebo to match SEL 6 mg
* Drug: Placebo to match SEL 18 mg


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Liver biopsy consistent with NASH and cirrhosis (F4 fibrosis) according to the NASH Clinical Research Network (CRN) classification, in the opinion of the central reader Has the following laboratory parameters at the screening visit, as determined by the central laboratory: Alanine aminotransferase (ALT) ≤ 8 x upper limit of normal (ULN) Creatinine Clearance (CLcr) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation HbA1c ≤ 9.5% (or serum fructosamine ≤ 381 micromole (μmol) if HbA1c is unable to be resulted) International normalised ratio (INR) ≤ 1.4, unless due to therapeutic anti-coagulation Platelet count ≥ 100,000/μL Key Exclusion Criteria: Prior history of decompensated liver disease including clinical ascites, hepatic encephalopathy (HE), or variceal bleeding Child-Pugh (CP) score > 7, as determined at screening, unless due to therapeutic anti-coagulation Model for End-stage Liver Disease (MELD) score > 12, as determined at screening, unless due to therapeutic anti-coagulation Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders, drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitrypsin deficiency, based on medical history and/or centralized review of liver histology. History of liver transplantation Current or history of hepatocellular carcinoma (HCC) Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SEL 6 mg<br>Randomized Phase: SEL 6 mg plus placebo to match SEL 18 mg for up to 240 weeks. Open-Label (OL) Phase: Participants who experienced a hepatic clinical event during the randomized phase prior to completing the Week 240 visit, will be offered the option to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the Randomized Phase. | Drug: SEL<br>* Tablets administered orally once daily<br>* Other names: GS-4997;Drug: Placebo to match SEL 18 mg<br>* Tablets administered orally once daily<br>|
| Experimental: SEL 18 mg<br>Randomized Phase: SEL 18 mg plus placebo to match SEL 6 mg for up to 240 weeks. Open-Label Phase: Participants who experienced a hepatic clinical event during the randomized phase prior to completing the Week 240 visit, will be offered the option to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the Randomized Phase. | Drug: SEL<br>* Tablets administered orally once daily<br>* Other names: GS-4997;Drug: Placebo to match SEL 6 mg<br>* Tablets administered orally once daily<br>|
| Placebo Comparator: Placebo<br>Randomized Phase: Placebo to match SEL 6 mg plus placebo to match SEL 18 mg for up to 240 weeks. Open-Label Phase: Participants who experienced a hepatic clinical event during the randomized phase prior to completing the Week 240 visit, will be offered the option to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the Randomized Phase. | Drug: Placebo to match SEL 6 mg<br>* Tablets administered orally once daily<br>Drug: Placebo to match SEL 18 mg<br>* Tablets administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. | Week 48 | 
| Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event | EFS was assessed by the time to the first clinical event, including liver decompensation events, liver transplantation and all-cause mortality. | Week 240 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the NAS criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. | Week 240 | 
| Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). | Week 48 | 
| Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240 | Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). | Week 240 | 
| Percentage of Participants Who Had NASH Resolution at Week 48 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. | Week 48 | 
| Percentage of Participants Who Had NASH Resolution at Week 240 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions.As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. | Week 240 |