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Safety and Efficacy of Selonsertib in Adults With Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis (STELLAR-3)

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ClinicalTrials.gov Identifier: NCT03053050
Recruitment Status : Terminated (This study was terminated early due to lack of efficacy based on the results of the Week 48 analysis as prespecified in the clinical study protocol.)
First Posted : February 14, 2017
Results First Posted : June 29, 2020
Last Update Posted : June 29, 2020
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Nonalcoholic Steatohepatitis Drug: SEL Drug: Placebo to match SEL 6 mg Drug: Placebo to match SEL 18 mg Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 808 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
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
Actual Study Start Date : February 13, 2017
Actual Primary Completion Date : June 19, 2019
Actual Study Completion Date : June 19, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: SEL 18 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.

Drug: SEL
Tablets administered orally once daily
Other Names:
  • selonsertib
  • GS-4997

Drug: Placebo to match SEL 6 mg
Tablets administered orally once daily

Experimental: SEL 6 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.

Drug: SEL
Tablets administered orally once daily
Other Names:
  • selonsertib
  • GS-4997

Drug: Placebo to match SEL 18 mg
Tablets administered orally once daily

Placebo Comparator: Placebo

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
Tablets administered orally once daily

Drug: Placebo to match SEL 18 mg
Tablets administered orally once daily




Primary Outcome Measures :
  1. 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 [ Time Frame: 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.

  2. Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event [ Time Frame: 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.


Secondary Outcome Measures :
  1. Percentage of Participants Who Had Progression to Cirrhosis at Week 48 [ Time Frame: Week 48 ]
    Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from < 4 at baseline to 4 at Week 48.

  2. Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240 [ Time Frame: 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.

  3. Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48 [ Time Frame: 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).

  4. Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240 [ Time Frame: 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).

  5. Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48 [ Time Frame: 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.

  6. Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 240 [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03053050


Locations
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Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol  [PDF] May 31, 2018
Statistical Analysis Plan  [PDF] January 23, 2019

Publications of Results:
Alkhouri N, Younossi ZM, Lawitz EJ, Wong VWS, Romero-Gomez M, et al. Impact of age on routinely available noninvasive tests for the discrimination of advanced fibrosis due to NASH in the phase 3 STELLAR trials of the ASK1 inhibitor selonsertib [Poster SAT-273]. European Association for the Study of the Liver (EASL); 2019; Vienna Austria.
Anstee QM, Lawitz EJ, Alkhouri N, Wai Sun Wong V, Romero-Gomez M, et al. Routinely available noninvasive tests discriminate advanced fibrosis due to NASH in the Phase 3 STELLAR trials of the ASK1 inhibitor selonsertib [poster]. American Association for the Study of Liver Diseases (AASLD); 2018, San Francisco, CA.
Younossi ZM, Lawitz E, Alkhouri N, Wong VWS, Romero-Gomez M, et al. Algorithms using noninvasive tests can accurately identify patients with advanced fibrosis due to NASH: Data From the STELLAR clinical trials [Poster LB-10]. AASLD; 2018; San Francisco, CA.
Younossi ZM, Stepanova M, Anstee QM, Lawitz EJ, Wai-Sun Wong V, et al. Severe impairment of patient-reported outcomes in patients with advanced fibrosis due to non-alcoholic steatohepatitis (NASH) [Poster]. AASLD; 2018; San Francisco, CA.
Younossi ZM, Stepanova M, Anstee QM, Lawitz EJ, Wai Sun Wong V, et al. Advanced fibrosis based on noninvasive tests in nonalcoholic steatohepatitis (NASH) is associated with impairment of patient-reported outcomes [Poster]. AASLD; 2018; San Francisco, CA.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT03053050    
Other Study ID Numbers: GS-US-384-1943
2016-004374-18 ( EudraCT Number )
First Posted: February 14, 2017    Key Record Dates
Results First Posted: June 29, 2020
Last Update Posted: June 29, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Selonsertib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action