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Study to Evaluate the Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (ATLAS)

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ClinicalTrials.gov Identifier: NCT03449446
Recruitment Status : Completed
First Posted : February 28, 2018
Results First Posted : December 3, 2020
Last Update Posted : December 3, 2020
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:

The primary objectives of this study are:

  • To assess the safety and tolerability of selonsertib (SEL), firsocostat (FIR) and cilofexor (CILO), administered alone or in combination, in participants with bridging fibrosis or compensated cirrhosis due to NASH
  • To evaluate changes in liver fibrosis, without worsening of NASH

Condition or disease Intervention/treatment Phase
Nonalcoholic Steatohepatitis Drug: SEL Drug: FIR Drug: CILO Drug: Placebo to match FIR Drug: Placebo to match CILO Drug: Placebo to match SEL Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 395 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib, GS-0976, GS-9674, and Combinations in Subjects With Bridging (F3) Fibrosis or Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)
Actual Study Start Date : March 21, 2018
Actual Primary Completion Date : October 30, 2019
Actual Study Completion Date : November 19, 2019


Arm Intervention/treatment
Experimental: Selonsertib (SEL)
Participants will receive SEL + placebo to match firsocostat 20 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 48 weeks.
Drug: SEL
18 mg tablet administered orally once daily without regard to food

Drug: Placebo to match FIR
Tablet administered orally once daily without regard to food

Drug: Placebo to match CILO
Tablet administered orally once daily without regard to food

Experimental: Firsocostat (FIR)
Participants will receive placebo to match SEL 18 mg tablet + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Drug: FIR
20 mg tablet administered orally once daily without regard to food
Other Name: GS-0976

Drug: Placebo to match CILO
Tablet administered orally once daily without regard to food

Drug: Placebo to match SEL
Tablet administered orally once daily without regard to food

Experimental: Cilofexor (CILO)
Participants will receive placebo to match SEL 18 mg tablet + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Drug: CILO
30 mg tablet administered orally once daily without regard to food
Other Name: GS-9674

Drug: Placebo to match FIR
Tablet administered orally once daily without regard to food

Drug: Placebo to match SEL
Tablet administered orally once daily without regard to food

Experimental: Selonsertib (SEL) + Firsocostat (FIR)
Participants will receive SEL + FIR + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Drug: SEL
18 mg tablet administered orally once daily without regard to food

Drug: FIR
20 mg tablet administered orally once daily without regard to food
Other Name: GS-0976

Drug: Placebo to match CILO
Tablet administered orally once daily without regard to food

Experimental: Selonsertib (SEL) + Cilofexor (CILO)
Participants will receive SEL + placebo to match FIR 20 mg tablet + CILO orally once daily for 48 weeks.
Drug: SEL
18 mg tablet administered orally once daily without regard to food

Drug: CILO
30 mg tablet administered orally once daily without regard to food
Other Name: GS-9674

Drug: Placebo to match FIR
Tablet administered orally once daily without regard to food

Experimental: Firsocostat (FIR) + Cilofexor (CILO)
Participants will receive placebo to match SEL 18 mg tablet + FIR + CILO orally once daily for 48 weeks.
Drug: FIR
20 mg tablet administered orally once daily without regard to food
Other Name: GS-0976

Drug: CILO
30 mg tablet administered orally once daily without regard to food
Other Name: GS-9674

Drug: Placebo to match SEL
Tablet administered orally once daily without regard to food

Experimental: Placebo
Participants will receive placebo to match SEL 18 mg + placebo to match FIR 20 mg tablet + placebo to match CILO 30 mg tablet orally once daily for 48 weeks.
Drug: Placebo to match FIR
Tablet administered orally once daily without regard to food

Drug: Placebo to match CILO
Tablet administered orally once daily without regard to food

Drug: Placebo to match SEL
Tablet administered orally once daily without regard to food




Primary Outcome Measures :
  1. Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: First dose date up to 48 weeks plus 30 days ]
  2. Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [ Time Frame: First dose date up to 48 weeks plus 30 days ]
    Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. Participants with any laboratory abnormality were reported.

  3. Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis 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 clinical research network classification (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. The 95% CI was based on the Clopper-Pearson method.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Liver biopsy consistent with NASH and F3 or F4 in the opinion of the central reader
  • In participants who have never had a liver biopsy, liver stiffness by FibroScan® ≥ 14.0 kPa and Enhanced Liver Fibrosis (ELF™) Test score ≥ 9.8 at Screening
  • Screening laboratory parameters, as determined by the central laboratory:

    • Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft-Gault equation
    • Hemoglobin A1c (HbA1c) ≤ 9.5%
    • Alanine aminotransferase (ALT) < 5 x Upper Limits of Normal (ULN)
    • Platelet count ≥ 125,000/μL

Key Exclusion Criteria:

  • Prior history of decompensated liver disease including ascites, hepatic encephalopathy, or variceal bleeding
  • Child-Pugh (CP) score > 6 at Screening, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation
  • Model for End-Stage Liver Disease (MELD) score > 12 at Screening, unless due to an alternate etiology such as therapeutic anticoagulation
  • Other causes of liver disease based on medical history and/or centralized review of liver histology, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment
  • History of liver transplantation
  • Current or prior history of hepatocellular carcinoma

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): NCT03449446


Locations
Show Show 101 study locations
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] April 25, 2019
Statistical Analysis Plan  [PDF] May 22, 2019

Publications of Results:
Loomba R, et al. Safety and efficacy of combination therapies including cilofexor/firsocostat in patients with bridging fibrosis and cirrhosis due to NASH: Results of the Phase 2b ATLAS trial [accepted for oral presentation]. European Association for the Study of the Liver (EASL); 2020; Virtual.
Loomba R, Alkhouri N, Strasser S, Wong VWS, Schall RA, McColgan B, et al. Clinical utility and application of non-invasive tests of fibrosis in the selection of patients with advanced fibrosis due to NASH in the Phase 2 ATLAS trial (Poster SAT-315). EASL; 2019; Vienna, Austria.
Loomba R, Alkhouri N, Patel K, Zhang J, McColgan BJ, Djedjos S, et al. Validation of Cutoffs for Controlled Attenuation Parameter with MRI-Proton Density Fat Fraction (PDFF) as a Reference Standard in Subjects with Nonalcoholic Steatohepatitis (NASH) Across Multiple Randomized, Controlled Trials (Poster 1727). American Association for the Study of Liver Diseases (AASLD); 2019; Boston, MA, USA.
Loomba R, Alkhouri N, Noureddin M, Zhang J, McColgan BJ, Djedjos S, et al. Validation of the Diagnostic Accuracy of Magnetic Resonance Elastography (MRE) for the Detection of Advanced Fibrosis Due to Nash Across Multiple Phase 2 and 3 Clinical Trials (Poster 1728). AASLD; 2019; Boston, MA, USA.
Alkhouri N, Strasser SI, Wong VWS, Aguilar R, Chuang J, Huss R, et al. Alcohol use is Underreported in Clinical Trials of NASH: Baseline Alcohol Biomarkers from a Phase 2 Clinical Trial (Poster 1765). AASLD; 2019; Boston, MA, USA.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT03449446    
Other Study ID Numbers: GS-US-454-4378
First Posted: February 28, 2018    Key Record Dates
Results First Posted: December 3, 2020
Last Update Posted: December 3, 2020
Last Verified: December 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
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Firsocostat
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action