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Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Participants With Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

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ClinicalTrials.gov Identifier: NCT04971785
Recruitment Status : Recruiting
First Posted : July 21, 2021
Last Update Posted : March 1, 2023
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
Gilead Sciences

Study Description
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Brief Summary:
The primary objective of this study is to evaluate whether the combination of semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR) causes fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with compensated cirrhosis due to NASH.

Condition or disease Intervention/treatment Phase
Nonalcoholic Steatohepatitis Drug: Semaglutide (SEMA) Drug: Cilofexor (CILO)/Firsocostat (FIR) Drug: PTM SEMA Drug: PTM CILO/FIR Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Subjects With Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)
Actual Study Start Date : August 9, 2021
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Semaglutide

Arms and Interventions
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Arm Intervention/treatment
Experimental: SEMA + CILO/FIR FDC
Participants will receive semaglutide (SEMA) 0.24-2.4 mg once weekly (dose escalation every 4 weeks) and fixed-dose combination (FDC) of cilofexor and firsocostat (CILO/FIR 30 mg/20 mg) once daily for 72 weeks
 Drug: Semaglutide (SEMA)
Administered as subcutaneous (SC) injection

Drug: Cilofexor (CILO)/Firsocostat (FIR)
Tablets administered orally
Other Name: GS-9674/GS-0976
Experimental: SEMA + Placebo-To-Match (PTM) CILO/FIR
Participants will receive SEMA 0.24-2.4 mg once weekly (dose escalation every 4 weeks) and PTM CILO/FIR administered once daily for 72 weeks
 Drug: Semaglutide (SEMA)
Administered as subcutaneous (SC) injection

Drug: PTM CILO/FIR
Tablets administered orally
Experimental: PTM SEMA + CILO/FIR FDC
PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks
 Drug: Cilofexor (CILO)/Firsocostat (FIR)
Tablets administered orally
Other Name: GS-9674/GS-0976

Drug: PTM SEMA
Administered as SC injection
Placebo Comparator: PTM SEMA + PTM CILO/FIR
PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks
 Drug: PTM SEMA
Administered as SC injection

Drug: PTM CILO/FIR
Tablets administered orally


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Participants Who Achieve ≥ 1-Stage Improvement in Fibrosis According to the NASH Clinical Research Network (CRN) Classification Without Worsening of NASH in Participants Treated With SEMA + CILO/FIR Versus Placebo [ Time Frame: Week 72 ]
    Worsening of NASH is defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation.

  2. Percentage of Participants With NASH Resolution in Participants Treated with SEMA+CILO/FIR Versus Placebo [ Time Frame: Week 72 ]
    NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0.


Secondary Outcome Measures :
  1. Percentage of Participants With NASH Resolution In Participants Treated With SEMA+CILO/FIR Versus CILO/FIR Alone [ Time Frame: Week 72 ]
  2. Percentage of Participants Who Achieve ≥1-Stage Improvement in Fibrosis (According to the NASH CRN Classification) Without Worsening of NASH in Participants Treated With SEMA+CILO/FIR Versus SEMA Alone [ Time Frame: Week 72 ]
    Worsening of NASH is defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation.


Eligibility Criteria
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Information from the National Library of Medicine

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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 cirrhosis (F4) due to NASH in the opinion of the central reader. In participants who have never had a liver biopsy, a screening liver biopsy may be performed

  • Screening laboratory parameters as determined by the study central laboratory:

    • Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m^2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation
    • HbA1c ≤ 10%
    • INR ≤ 1.4, unless due to therapeutic anticoagulation
    • Platelet count ≥ 125,000/uL
    • Alanine Aminotransferase (ALT) < 5 x ULN
    • Serum albumin ≥ 3.5 g/dL
    • Serum Alkaline Phosphatase (ALP) ≤ 2 x ULN
  • BMI ≥ 23 kg/m^2 at screening

Key Exclusion Criteria:

  • Prior history of decompensated liver disease, including ascites, hepatic encephalopathy (HE), 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 alternative etiology such as therapeutic anticoagulation
  • Other causes of liver disease based on medical history and/or central reader review of liver histology, including but not limited to: alcoholic liver disease, 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
  • Chronic HBV infection (HBsAg positive), or Chronic HCV infection (HCV antibody and HCV RNA positive). Participants cured of HCV infection less than 2 years prior to the screening visit are not eligible
  • History of liver transplantation
  • Current or prior history of hepatocellular carcinoma (HCC)

  • Men who habitually drink greater than 21 units/week of alcohol or women who habitually drink greater than 14 units/week of alcohol (one unit is equivalent to 12 oz/360 mL of beer, a 4 oz/120 mL glass of wine, or 1 oz/30 mL of hard liquor).

    • For individuals on vitamin E regimen ≥ 800 IU/day, or pioglitazone, dose must be stable, in the opinion of the investigator for at least 180 days prior to the historical or screening liver biopsy
    • For individuals on medications for diabetes, dose must be stable, in the opinion of the investigator, for at least 90 days prior to the historical or screening liver biopsy
  • History of type 1 diabetes
  • Treatment with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in the period from 90 days prior to the screening visit and for individuals with a qualifying historical liver biopsy, for 90 days prior to the date of the historical liver biopsy
  • For participants who have not completed a series of an authorized COVID-19 vaccination regimen prior to screening, a positive result for COVID-19 on SARS-CoV-2 RT-PCR test

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

Contacts and Locations
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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): NCT04971785


Contacts
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Contact: Gilead Clinical Study Information Center 1-833-445-3230 (GILEAD-0) GileadClinicalTrials@gilead.com

Locations
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Sponsors and Collaborators
Gilead Sciences
Novo Nordisk A/S
Investigators
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Study Director: Gilead Study Director Gilead Sciences
More Information
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Additional Information:

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT04971785    
Other Study ID Numbers: GS-US-454-6075
2021-001445-12 ( EudraCT Number )
jRCT2071210112 ( Registry Identifier: jRCT )
First Posted: July 21, 2021    Key Record Dates
Last Update Posted: March 1, 2023
Last Verified: February 2023
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
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