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)

Overview

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.

Full Title of Study: “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)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: March 2024

Interventions

  • Drug: Semaglutide (SEMA)
    • Administered as subcutaneous (SC) injection
  • Drug: Cilofexor (CILO)/Firsocostat (FIR)
    • Tablets administered orally
  • Drug: PTM SEMA
    • Administered as SC injection
  • Drug: PTM CILO/FIR
    • Tablets administered orally

Arms, Groups and Cohorts

  • 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
  • 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
  • Experimental: PTM SEMA + CILO/FIR FDC
    • PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks
  • Placebo Comparator: PTM SEMA + PTM CILO/FIR
    • PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks

Clinical Trial Outcome Measures

Primary Measures

  • 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.
  • 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 Measures

  • Percentage of Participants With NASH Resolution In Participants Treated With SEMA+CILO/FIR Versus CILO/FIR Alone
    • Time Frame: Week 72
  • 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.

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Gilead Sciences
  • Collaborator
    • Novo Nordisk A/S
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Gilead Study Director, Study Director, Gilead Sciences
  • Overall Contact(s)
    • Gilead Clinical Study Information Center, 1-833-445-3230 (GILEAD-0), GileadClinicalTrials@gilead.com

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