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Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH)

Primary Purpose

Nonalcoholic Steatohepatitis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Semaglutide
Firsocostat
Cilofexor
Sponsored by
Gilead Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nonalcoholic Steatohepatitis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

  • Historical liver biopsy consistent with NASH with stage 2-3 fibrosis according to NASH Clinical Research Network (CRN) classification OR clinical diagnosis of nonalcoholic fatty liver disease and screening FibroTest, magnetic resonance imaging - proton density fat fraction (MRI-PDFF), and FibroScan

  • Screening laboratory parameters, as determined by central laboratory:

    • Alanine aminotransferase (ALT) ≤ 5 x upper limit of the normal range (ULN)
    • Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Modification of Diet in Renal Disease (MDRD) study equation
    • HbA1c ≤ 9.5%
    • International normalized ratio (INR) ≤ 1.2, unless due to therapeutic anti-coagulation therapy
    • Platelet count ≥ 100,000/μL
    • Total bilirubin < 1.3 x ULN unless alternate etiology such as Gilbert's syndrome present
    • Calcitonin ≤ 100 ng/L
  • Body Mass Index (BMI) > 23 kg/m^2 and body weight of > 60 kg

Key Exclusion Criteria:

  • Any historical liver biopsy consistent with cirrhosis
  • Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding
  • Other causes of liver disease, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment
  • History of liver transplantation
  • History of hepatocellular carcinoma
  • History of pancreatitis (acute or chronic)
  • Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
  • Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the period from 90 days prior to the date of the Screening Visit
  • Individuals on antidiabetic medications must be on a stable dose for at least 90 days prior to the date of the Screening Visit and in the period between the date of the Screening Visit and Enrollment (Day -14)

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Sites / Locations

  • Institute for Liver Health - Arizona Liver Health
  • Southern California Research Centers
  • University of California San Diego (UCSD)
  • Ruane Clinical Research Group, Inc
  • Cedars Sinai Medical Center
  • Inland Empire Clinical Trials, LLC
  • Medical Associates Research Group
  • Gastrointestinal Specialists of Georgia
  • Beth Israel Deaconess Medical Center
  • Jubilee Clinical Research, Inc.
  • Northwell Health
  • Gastro One
  • University Gastroenterology
  • Gastro One
  • Quality Medical Research, PLLC
  • Texas Clinical Research Institute
  • The Liver Institute at Methodist Dallas Medical Center
  • American Research Corporation

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Semaglutide

Semaglutide + Firsocostat 20 mg

Semaglutide + Cilofexor 30 mg

Semaglutide + Cilofexor 100 mg

Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg

Arm Description

Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks

Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks

Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks

Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks

Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks

Outcomes

Primary Outcome Measures

Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0.

Secondary Outcome Measures

Full Information

First Posted
June 12, 2019
Last Updated
June 25, 2021
Sponsor
Gilead Sciences
Collaborators
Novo Nordisk A/S
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1. Study Identification

Unique Protocol Identification Number
NCT03987074
Brief Title
Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH)
Official Title
A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
July 29, 2019 (Actual)
Primary Completion Date
July 13, 2020 (Actual)
Study Completion Date
July 13, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
Collaborators
Novo Nordisk A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonalcoholic Steatohepatitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
109 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Semaglutide
Arm Type
Experimental
Arm Description
Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks
Arm Title
Semaglutide + Firsocostat 20 mg
Arm Type
Experimental
Arm Description
Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks
Arm Title
Semaglutide + Cilofexor 30 mg
Arm Type
Experimental
Arm Description
Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks
Arm Title
Semaglutide + Cilofexor 100 mg
Arm Type
Experimental
Arm Description
Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks
Arm Title
Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg
Arm Type
Experimental
Arm Description
Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks
Intervention Type
Drug
Intervention Name(s)
Semaglutide
Intervention Description
Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly
Intervention Type
Drug
Intervention Name(s)
Firsocostat
Other Intervention Name(s)
GS-0976
Intervention Description
Tablets administered orally once daily
Intervention Type
Drug
Intervention Name(s)
Cilofexor
Other Intervention Name(s)
GS-9674
Intervention Description
Tablets administered orally once daily
Primary Outcome Measure Information:
Title
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
Description
Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time Frame
First dose date up to Week 24 plus 30 days
Title
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
Description
Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0.
Time Frame
First dose date up to 24 weeks plus 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria: Historical liver biopsy consistent with NASH with stage 2-3 fibrosis according to NASH Clinical Research Network (CRN) classification OR clinical diagnosis of nonalcoholic fatty liver disease and screening FibroTest, magnetic resonance imaging - proton density fat fraction (MRI-PDFF), and FibroScan Screening laboratory parameters, as determined by central laboratory: Alanine aminotransferase (ALT) ≤ 5 x upper limit of the normal range (ULN) Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Modification of Diet in Renal Disease (MDRD) study equation HbA1c ≤ 9.5% International normalized ratio (INR) ≤ 1.2, unless due to therapeutic anti-coagulation therapy Platelet count ≥ 100,000/μL Total bilirubin < 1.3 x ULN unless alternate etiology such as Gilbert's syndrome present Calcitonin ≤ 100 ng/L Body Mass Index (BMI) > 23 kg/m^2 and body weight of > 60 kg Key Exclusion Criteria: Any historical liver biopsy consistent with cirrhosis Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding Other causes of liver disease, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment History of liver transplantation History of hepatocellular carcinoma History of pancreatitis (acute or chronic) Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the period from 90 days prior to the date of the Screening Visit Individuals on antidiabetic medications must be on a stable dose for at least 90 days prior to the date of the Screening Visit and in the period between the date of the Screening Visit and Enrollment (Day -14) Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
Institute for Liver Health - Arizona Liver Health
City
Chandler
State/Province
Arizona
ZIP/Postal Code
85224
Country
United States
Facility Name
Southern California Research Centers
City
Coronado
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
University of California San Diego (UCSD)
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Ruane Clinical Research Group, Inc
City
Los Angeles
State/Province
California
ZIP/Postal Code
90036
Country
United States
Facility Name
Cedars Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
Inland Empire Clinical Trials, LLC
City
Rialto
State/Province
California
ZIP/Postal Code
92377
Country
United States
Facility Name
Medical Associates Research Group
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Name
Gastrointestinal Specialists of Georgia
City
Marietta
State/Province
Georgia
ZIP/Postal Code
30060
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Jubilee Clinical Research, Inc.
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89109
Country
United States
Facility Name
Northwell Health
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Facility Name
Gastro One
City
Huntersville
State/Province
North Carolina
ZIP/Postal Code
28078
Country
United States
Facility Name
University Gastroenterology
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02905
Country
United States
Facility Name
Gastro One
City
Germantown
State/Province
Tennessee
ZIP/Postal Code
38138
Country
United States
Facility Name
Quality Medical Research, PLLC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37211
Country
United States
Facility Name
Texas Clinical Research Institute
City
Arlington
State/Province
Texas
ZIP/Postal Code
76012
Country
United States
Facility Name
The Liver Institute at Methodist Dallas Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75203
Country
United States
Facility Name
American Research Corporation
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
Citation
Alkhouri N et al. Safety and Efficacy of Combination Therapies Including Semaglutide, Cilofexor, and Firsocostat in Patients with NASH [accepted for oral presentation]. American Association for the Study of Liver Diseases (AASLD); 2020; Virtual.
Results Reference
result
PubMed Identifier
35439567
Citation
Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, Huss RS, Zhu Y, Billin AN, Damgaard LH, Buchholtz K, Kjaer MS, Balendran C, Myers RP, Loomba R, Noureddin M. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol. 2022 Sep;77(3):607-618. doi: 10.1016/j.jhep.2022.04.003. Epub 2022 Apr 16.
Results Reference
derived

Learn more about this trial

Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH)

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