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

Phase 3

Terminated

• Conditions: Nonalcoholic Steatohepatitis
• Interventions: Drug: SEL; Drug: Placebo to match SEL 6 mg; Drug: Placebo to match SEL 18 mg

• Registration Number: NCT03053050
• Lead Sponsor: Gilead Sciences

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-02-10
• Study First Submitted QC: 2017-02-10
• Study Start: 2017-02-13
• Study First Posted: 2017-02-14
• Primary Completion: 2019-06-19
• Study Completion: 2019-06-19
• Status Verified: 2020-06
• Results First Submitted: 2020-06-10
• Results First Submitted QC: 2020-06-10
• Last Update Submitted: 2020-06-10
• Results First Posted: 2020-06-29
• Last Update Posted: 2020-06-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 808

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SEL 18 mg	Placebo to match SEL 6 mg	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.
SEL 18 mg	SEL	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.
SEL 6 mg	SEL	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.
Placebo	Placebo to match SEL 6 mg	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.
SEL 6 mg	Placebo to match SEL 18 mg	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.
Placebo	Placebo to match SEL 18 mg	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.

Primary Outcome Measures

Name	Time	Method
Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event	Week 240	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.
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	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48	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).
Percentage of Participants Who Had Progression to Cirrhosis at Week 48	Week 48	Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from \< 4 at baseline to 4 at Week 48.
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240	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).
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240	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.
Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48	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.
Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 240	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.

Trial Locations

Locations (290)

Institute of Liver Health; 🇺🇸 Chandler, Arizona, United States

Banner University Medical Center-Phoenix; 🇺🇸 Phoenix, Arizona, United States

St. Joseph's Hospital and Medical Center; 🇺🇸 Phoenix, Arizona, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

University of Arizona; 🇺🇸 Tucson, Arizona, United States

Baptist Medical Center; 🇺🇸 Little Rock, Arkansas, United States

Arkansas Gastroenterology; 🇺🇸 North Little Rock, Arkansas, United States

eStudySite; 🇺🇸 Pittsburgh, Pennsylvania, United States

Southern California Liver Centers; 🇺🇸 Coronado, California, United States

United Gastroenterologists; 🇺🇸 Costa Mesa, California, United States

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