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)

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)

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

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: SEL; Drug: Placebo to match FIR; Drug: Placebo to match CILO; Drug: FIR; Drug: Placebo to match SEL; Drug: CILO

• Study Type: Interventional
• Enrollment (Actual): 395
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Camperdown, Australia, 2050
    • Royal Prince Alfred Hospital
  • Darlinghurst, Australia, 2010
    • St Vincent's Hospital Sydney
  • Heidelberg, Australia, 3084
    • Austin Health
  • Melbourne, Australia, 3004
    • The Alfred Hospital, Alfred Health
  • Westmead, Australia, 2145
    • Westmead Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane & Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health, Monash Medical Centre
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
    • Parkville, Victoria, Australia, 3050
      • Melbourne Health, Royal Melbourne Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Canada
  • Brampton, Canada, L6R 3J7
    • William Osler Health System-Brampton Civic Hospital
  • Calgary, Canada, T2N 4Z6
    • University of Calgary Liver Unit (Heritage Medical Research Clinic)
  • Montreal, Canada, H4A 3J1
    • Chronic Viral Illness Service McGill University Health Centre (MUHC)/ Royal Victoria Hospital
  • Toronto, Canada, M6H 3M1
    • Toronto Liver Centre
  • Toronto, Canada, M5G 2C4
    • Toronto General Hospital
• Hong Kong
  • Shatin, Hong Kong
    • Prince of Wales Hospital
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Fundacion de Investigacion de Diego
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224-5688
      • The Institute for Liver Health
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona, Mayo Clinic Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Liver Wellness Center
    • North Little Rock, Arkansas, United States, 72117
      • Arkansas Gastroenterology
  • California
    • Chula Vista, California, United States, 91911-6660
      • eStudySite
    • Coronado, California, United States, 92118
      • Southern California Liver Center
    • Fresno, California, United States, 93720
      • Fresno Clinical Research Center
    • La Jolla, California, United States, 92037
      • UCSD NAFLD Clinical Research Center
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group Inc.
    • Los Angeles, California, United States, 99352
      • Cedars-Sinai Medical Center
    • Pasadena, California, United States, 91105
      • California Liver Research Institute
    • Pasadena, California, United States, 91105
      • Huntington Medical Research Institutes Liver Center
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center (Study Visits)
    • San Diego, California, United States, 92123
      • Medical Associates Research Group
  • Colorado
    • Englewood, Colorado, United States, 80113
      • South Denver Gastroenterology, PC
  • Florida
    • Doral, Florida, United States, 33166
      • Integrity Clinical Research
    • Gainesville, Florida, United States, 32610
      • UF Hepatology Research at CTRB
    • Miami, Florida, United States, 33165
      • Genoma Research Group
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Diseases/University of Miami
    • Miami, Florida, United States, 33157
      • IMIC Inc
    • Tampa, Florida, United States, 34211
      • Florida Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Digestive Healthcare of Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Hospital
    • Columbus, Georgia, United States, 31904
      • Gastrointestinal Diseases Research
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University; Feinberg School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indianapolis Gastroenterology Research Foundation
  • Iowa
    • Clive, Iowa, United States, 50325
      • Iowa Digestive Disease Center, P.C.
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • Bastrop, Louisiana, United States, 71220
      • Delta Research Partners, LLC
    • New Orleans, Louisiana, United States, 70112
      • Tulane University
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Catonsville, Maryland, United States, 21228
      • Digestive Disease Associates, PA
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health Systems
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Ridgeland, Mississippi, United States, 39157
      • Southern Therapy and Advanced Research (STAR) LLC
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Jubilee Clinical Research, Inc.
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School- Doctors Office Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Manhasset, New York, United States, 11030
      • Sandra Atlas Bass Center for Liver Diseases and Transplantation
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • NYU Langone Health
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • New York, New York, United States, 10003
      • Icahn School of Medicine at Mount Sinai Beth Israel
    • New York, New York, United States, 10016
      • Concorde Medical Group, PLLC
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Carolinas Healthcare System Center for Liver Disease and Transplant
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center, Duke South Clinics
    • Fayetteville, North Carolina, United States, 28304
      • Cumberland Research Associates, LLC
  • Ohio
    • Cincinnati, Ohio, United States, 45249
      • Consultants for Clinical Research wed
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania- Perelman Center for Advanced Medicine
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC - Center for Liver Diseases at the Thomas E. Starlz Institute
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • University Gastroenterology
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (Liver Biopsy)
    • Greenville, South Carolina, United States, 29605
      • GHS Gastroenterology and Liver Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Gastro One
    • Nashville, Tennessee, United States, 37211
      • Quality Medical Research, PLLC
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute, LLC
    • Austin, Texas, United States, 78746
      • Pinnacle Clinical Research, PLLC
    • Austin, Texas, United States, 78758
      • Austin Center for Clinical Research
    • Dallas, Texas, United States, 75203
      • The Liver Institute At Methodist Dallas Medical Center
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center Internal Medicine Digestive and Liver Diseases Clinical Trials
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine - Advanced Liver Therapies
    • Live Oak, Texas, United States, 78233
      • Pinnacle Clinical Research
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at Texas Liver Institute
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Liver Disease and Transplant Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Medical Center
    • Falls Church, Virginia, United States, 22042
      • California Pacific Medical Center - Sutter Pacific Medical Foundation San Francisco Center for Liver Disease Dept. of Transplant
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists
    • Richmond, Virginia, United States, 23249
      • McGuire DVAMC
    • Richmond, Virginia, United States, 23226
      • Bon Secours Richmond Community Hospital, Inc. d/b/a Bon Secours Liver Institute of Richmond
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98104
      • Swedish Organ Transplant and Liver Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

7

Arms and Interventions

Participant Group / 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: Placebo to match CILO; Tablet administered orally once daily without regard to food; Drug: FIR; 20 mg tablet administered orally once daily without regard to food; Other Names: GS-0976; 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: 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; Drug: CILO; 30 mg tablet administered orally once daily without regard to food; Other Names: GS-9674
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: Placebo to match CILO; Tablet administered orally once daily without regard to food; Drug: FIR; 20 mg tablet administered orally once daily without regard to food; Other Names: GS-0976
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: Placebo to match FIR; Tablet administered orally once daily without regard to food; Drug: CILO; 30 mg tablet administered orally once daily without regard to food; Other Names: GS-9674
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 Names: GS-0976; Drug: Placebo to match SEL; Tablet administered orally once daily without regard to food; Drug: CILO; 30 mg tablet administered orally once daily without regard to food; Other Names: GS-9674
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)		First dose date up to 48 weeks plus 30 days
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities	Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. Participants with any laboratory abnormality were reported.	First dose date up to 48 weeks plus 30 days
Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at 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.	Week 48

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• 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.
• Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VW, Alkhouri N; ATLAS Investigators. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology. 2021 Feb;73(2):625-643. doi: 10.1002/hep.31622.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 21, 2018
• Primary Completion (ACTUAL): October 30, 2019
• Study Completion (ACTUAL): November 19, 2019

Study Registration Dates

• First Submitted: February 23, 2018
• First Submitted That Met QC Criteria: February 23, 2018
• First Posted (ACTUAL): February 28, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 3, 2020
• Last Update Submitted That Met QC Criteria: December 1, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Firsocostat
• Other Study ID Numbers: GS-US-454-4378

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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