Clinical trial NCT03449446: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2018-02-28
Enrollment: 395
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
timeFrame: First dose date up to 48 weeks plus 30 days
measure: Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
timeFrame: First dose date up to 48 weeks plus 30 days
measure: Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 48
timeFrame: Week 48
Secondary outcomes:
Other outcomes:
Locations:
city: Chandler
country: United States
facility: The Institute for Liver Health
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona, Mayo Clinic Hospital
state: Arizona
city: Little Rock
country: United States
facility: Liver Wellness Center
state: Arkansas
city: North Little Rock
country: United States
facility: Arkansas Gastroenterology
state: Arkansas
city: Chula Vista
country: United States
facility: eStudySite
state: California
city: Coronado
country: United States
facility: Southern California Liver Center
state: California
city: Fresno
country: United States
facility: Fresno Clinical Research Center
state: California
city: La Jolla
country: United States
facility: UCSD NAFLD Clinical Research Center
state: California
city: Los Angeles
country: United States
facility: Ruane Clinical Research Group Inc.
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Pasadena
country: United States
facility: California Liver Research Institute
state: California
city: Pasadena
country: United States
facility: Huntington Medical Research Institutes Liver Center
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: Sacramento
country: United States
facility: University of California, Davis Medical Center (study visits)
state: California
city: San Diego
country: United States
facility: Medical Associates Research Group
state: California
city: Englewood
country: United States
facility: South Denver Gastroenterology, PC
state: Colorado
city: Doral
country: United States
facility: Integrity Clinical Research
state: Florida
city: Gainesville
country: United States
facility: UF Hepatology Research at CTRB
state: Florida
city: Miami
country: United States
facility: Schiff Center for Liver Diseases/University of Miami
state: Florida
city: Miami
country: United States
facility: IMIC Inc
state: Florida
city: Miami
country: United States
facility: Genoma Research Group
state: Florida
city: Tampa
country: United States
facility: Florida Research Institute
state: Florida
city: Atlanta
country: United States
facility: Digestive Healthcare of Georgia
state: Georgia
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Columbus
country: United States
facility: Gastrointestinal Diseases Research
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Chicago
country: United States
facility: Northwestern University; Feinberg School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indianapolis Gastroenterology Research Foundation
state: Indiana
city: Clive
country: United States
facility: Iowa Digestive Disease Center, P.C.
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Bastrop
country: United States
facility: Delta Research Partners, LLC
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana Research Center, LLC
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Catonsville
country: United States
facility: Digestive Disease Associates, PA
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health Systems
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Ridgeland
country: United States
facility: Southern Therapy and Advanced Research (STAR) LLC
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Las Vegas
country: United States
facility: Jubilee Clinical Research, Inc.
state: Nevada
city: Newark
country: United States
facility: Rutgers New Jersey Medical School- Doctors Office Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Manhasset
country: United States
facility: Sandra Atlas Bass Center for Liver Diseases and Transplantation
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai Beth Israel
state: New York
city: New York
country: United States
facility: Concorde Medical Group, PLLC
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Charlotte
country: United States
facility: Carolinas Healthcare System Center for Liver Disease and Transplant
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center, Duke South Clinics
state: North Carolina
city: Fayetteville
country: United States
facility: Cumberland Research Associates, LLC
state: North Carolina
city: Cincinnati
country: United States
facility: Consultants for Clinical Research wed
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania- Perelman Center for Advanced Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC - Center for Liver Diseases at the Thomas E. Starlz Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System
state: Pennsylvania
city: Providence
country: United States
facility: University Gastroenterology
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina (Liver Biopsy)
state: South Carolina
city: Greenville
country: United States
facility: GHS Gastroenterology and Liver Center
state: South Carolina
city: Germantown
country: United States
facility: Gastro One
state: Tennessee
city: Nashville
country: United States
facility: Quality Medical Research, PLLC
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute, LLC
state: Texas
city: Austin
country: United States
facility: Pinnacle Clinical Research, PLLC
state: Texas
city: Austin
country: United States
facility: Austin Center for Clinical Research
state: Texas
city: Dallas
country: United States
facility: The Liver Institute at Methodist Dallas Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center Internal Medicine Digestive and Liver Diseases Clinical Trials
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Advanced Liver Therapies
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Live Oak
country: United States
facility: Pinnacle Clinical Research
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at Texas Liver Institute
state: Texas
city: Murray
country: United States
facility: Intermountain Liver Disease and Transplant Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Medical Center
state: Virginia
city: Falls Church
country: United States
facility: California Pacific Medical Center - Sutter Pacific Medical Foundation San Francisco Center for Liver Disease Dept. of Transplant
state: Virginia
city: Norfolk
country: United States
facility: Digestive and Liver Disease Specialists
state: Virginia
city: Richmond
country: United States
facility: Bon Secours Richmond Community Hospital, Inc. d/b/a Bon Secours Liver Institute of Richmond
state: Virginia
city: Richmond
country: United States
facility: McGuire DVAMC
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Organ Transplant and Liver Center
state: Washington
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Health, Monash Medical Centre
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Parkville
country: Australia
facility: Melbourne Health, Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
city: Heidelberg
country: Australia
facility: Austin Health
city: Melbourne
country: Australia
facility: The Alfred Hospital, Alfred Health
city: Westmead
country: Australia
facility: Westmead Hospital
city: Brampton
country: Canada
facility: William Osler Health System-Brampton Civic Hospital
city: Calgary
country: Canada
facility: University of Calgary Liver Unit (Heritage Medical Research Clinic)
city: Montreal
country: Canada
facility: Chronic Viral Illness Service McGill University Health Centre (MUHC)/ Royal Victoria Hospital
city: Toronto
country: Canada
facility: Toronto General Hospital
city: Toronto
country: Canada
facility: Toronto Liver Centre
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: San Juan
country: Puerto Rico
facility: Fundacion de Investigacion de Diego
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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; for the 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.