Safety and Efficacy of Selonsertib in Adults With Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce progression to cirrhosis and associated complications in adults with NASH and bridging (F3) fibrosis.

Official Title
-----------------
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib in Subjects With Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Liver biopsy consistent with NASH and bridging (F3 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: 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 Hemoglobin A1c (HbA1c) ≤ 9.5% (or serum fructosamine ≤ 381 μmol if HbA1c is unable to be resulted) Total bilirubin ≤ 1.3 x ULN (unless an alternate etiology such as Gilbert's syndrome or hemolytic anemia is present) Key Exclusion Criteria: Prior history of decompensated liver disease including clinical ascites, hepatic encephalopathy (HE), or variceal bleeding Child-Pugh (CP) score > 6, 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-antitryspin 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
-----------------
Minimum Age: 18 Years
Maximum Age: 70 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: SEL 18 mg<br>Randomized Phase: Selonsertib (SEL) 18 mg tablet + placebo to match SEL 6 mg tablet for 240 weeks Open-Label (OL) Phase: Participants who experience a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, will be offered the option to roll over into an OL phase to receive OL SEL 18 mg 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>|
| Experimental: SEL 6 mg<br>Randomized Phase: SEL 6 mg tablet + placebo to match SEL 18 mg tablet for 240 weeks OL Phase: Participants who experience a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, will be offered the option to roll over into an OL phase to receive OL SEL 18 mg 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>|
| Placebo Comparator: Placebo<br>Randomized Phase: Placebo to match SEL 6 mg tablet + placebo to match SEL 18 mg tablet for 240 weeks OL Phase: Participants who experience a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, will be offered the option to roll over into an OL phase to receive OL SEL 18 mg 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?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH 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). 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 progression to cirrhosis on liver biopsy, 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 Progression to Cirrhosis at Week 48 | Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from < 4 at baseline to 4 at Week 48. | Week 48 | 
| 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 Without Worsening of Fibrosis at Week 48 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN. | Week 48 | 
| Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 240 | NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN. | Week 240 |