Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

Phase 2

Completed

• Conditions: Nonalcoholic Steatohepatitis
• Interventions: Drug: PTM SEMA; Drug: Semaglutide (SEMA); Drug: Cilofexor (CILO)/Firsocostat (FIR); Drug: PTM CILO/FIR

• Registration Number: NCT04971785
• Lead Sponsor: Gilead Sciences

Brief Summary

The goals of this clinical study are to learn more about the study drugs, semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR), and understand whether they cause fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with cirrhosis due to NASH.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-07-20
• Study First Submitted QC: 2021-07-20
• Study First Posted: 2021-07-21
• Study Start: 2021-08-09
• Primary Completion: 2024-11-12
• Study Completion: 2024-12-09
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-07
• Last Update Posted: 2025-01-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 457

Inclusion Criteria

• Liver biopsy consistent with cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH) in the opinion of the central reader. In individuals 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%
  • International normalized ratio (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

• Body mass index (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 hepatitis B virus (HBV) infection (HBsAg positive), or Chronic hepatitis C virus (HCV) infection (HCV antibody and HCV ribonucleic acid (RNA) positive). Individuals 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 (1 unit is equivalent to 12 ounce (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 individuals who have not completed a series of an authorized coronavirus disease 2019 (COVID-19) vaccination regimen prior to screening, a positive result for COVID-19 on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) test.

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SEMA + CILO/FIR FDC	Cilofexor (CILO)/Firsocostat (FIR)	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
PTM SEMA + PTM CILO/FIR	PTM SEMA	PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks
SEMA + Placebo-To-Match (PTM) CILO/FIR	Semaglutide (SEMA)	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
SEMA + Placebo-To-Match (PTM) CILO/FIR	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
SEMA + CILO/FIR FDC	Semaglutide (SEMA)	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
PTM SEMA + PTM CILO/FIR	PTM CILO/FIR	PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks
PTM SEMA + CILO/FIR FDC	Cilofexor (CILO)/Firsocostat (FIR)	PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks
PTM SEMA + CILO/FIR FDC	PTM SEMA	PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks

Primary Outcome Measures

Name	Time	Method
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	Week 72	Worsening of NASH is defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With NASH Resolution In Participants Treated With SEMA+CILO/FIR Versus CILO/FIR Alone	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	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	Week 72	NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0.

Trial Locations

Locations (229)

University of Alabama at Birmingham Hospital; 🇺🇸 Birmingham, Alabama, United States

Digestive Health Specialists; 🇺🇸 Dothan, Alabama, United States

North Alabama Health Research, LLC; 🇺🇸 Madison, Alabama, United States

The Institution For Liver Health dba Arizona Liver Health; 🇺🇸 Tucson, Arizona, United States

Arizona Health Research; 🇺🇸 Chandler, Arizona, United States

The Institute for Liver Health DBA Arizona Liver Health; 🇺🇸 Peoria, Arizona, United States

Gastrointestinal Alliance - Sun City; 🇺🇸 Sun City, Arizona, United States

Adobe Clinical Research, LLC; 🇺🇸 Tucson, Arizona, United States

Arkansas Diagnostic Center; 🇺🇸 Little Rock, Arkansas, United States

ARCare Center for Clinical Research; 🇺🇸 Little Rock, Arkansas, United States

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