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

Phase 3

Terminated

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

• Registration Number: NCT03053063
• 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 associated complications in adults with cirrhosis due to NASH.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-01-30
• Study First Submitted: 2017-02-10
• Study First Submitted QC: 2017-02-10
• Study First Posted: 2017-02-14
• Primary Completion: 2019-05-06
• Study Completion: 2019-05-06
• Status Verified: 2020-04
• Results First Submitted: 2020-04-24
• Results First Submitted QC: 2020-04-24
• Last Update Submitted: 2020-04-24
• Results First Posted: 2020-05-07
• Last Update Posted: 2020-05-07

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 883

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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	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.
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 liver decompensation events, liver transplantation and all-cause mortality.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Had NASH Resolution at Week 48	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.
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 NASH Resolution at Week 240	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.
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 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.

Trial Locations

Locations (281)

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

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

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

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

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

Southern California Research Center; 🇺🇸 Coronado, California, United States

Fresno Clinical Research Center; 🇺🇸 Fresno, California, United States

Scripps Clinical Research Services; 🇺🇸 La Jolla, California, United States

University of California, San Diego (Altman Clinical and Translational Research Center); 🇺🇸 La Jolla, California, United States

Ruane Clinical Research Group; 🇺🇸 Los Angeles, California, United States

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