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

A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)

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

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Semaglutide; Drug: Firsocostat; Drug: Cilofexor

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Institute for Liver Health - Arizona Liver Health
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Centers
    • La Jolla, California, United States, 92093
      • University of California San Diego (UCSD)
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group, Inc
    • Rialto, California, United States, 92377
      • Inland Empire Clinical Trials, LLC
    • San Diego, California, United States, 92123
      • Medical Associates Research Group
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Jubilee Clinical Research, Inc.
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Gastro One
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • University Gastroenterology
  • 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
    • Dallas, Texas, United States, 75203
      • The Liver Institute At Methodist Dallas Medical Center
    • San Antonio, Texas, United States, 78215
      • American Research Corporation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide; Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks	Drug: Semaglutide; Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly
Experimental: Semaglutide + Firsocostat 20 mg; Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks	Drug: Semaglutide; Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly; Drug: Firsocostat; Tablets administered orally once daily; Other Names: GS-0976
Experimental: Semaglutide + Cilofexor 30 mg; Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks	Drug: Semaglutide; Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly; Drug: Cilofexor; Tablets administered orally once daily; Other Names: GS-9674
Experimental: Semaglutide + Cilofexor 100 mg; Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks	Drug: Semaglutide; Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly; Drug: Cilofexor; Tablets administered orally once daily; Other Names: GS-9674
Experimental: Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg; Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks	Drug: Semaglutide; Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly; Drug: Firsocostat; Tablets administered orally once daily; Other Names: GS-0976; Drug: Cilofexor; Tablets administered orally once daily; Other Names: GS-9674

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	First dose date up to Week 24 plus 30 days
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.	First dose date up to 24 weeks plus 30 days

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Collaborators: Novo Nordisk A/S

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2019
• Primary Completion (Actual): July 13, 2020
• Study Completion (Actual): July 13, 2020

Study Registration Dates

• First Submitted: June 12, 2019
• First Submitted That Met QC Criteria: June 12, 2019
• First Posted (Actual): June 14, 2019

Study Record Updates

• Last Update Posted (Actual): July 15, 2021
• Last Update Submitted That Met QC Criteria: June 25, 2021
• Last Verified: June 1, 2021

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-454-5533

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