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

• ClinicalTrials.gov Identifier: NCT04971785
• Recruitment Status: Active, not recruiting
• First Posted: July 21, 2021
• Last Update Posted: February 28, 2024
• Sponsor: Gilead Sciences
• Collaborator: Novo Nordisk A/S
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: July 20, 2021
• First Posted Date: July 21, 2021
• Last Update Posted Date: February 28, 2024
• Actual Study Start Date: August 9, 2021
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 26, 2024)

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.

Original Primary Outcome Measures (submitted: July 20, 2021)

• 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.

Current Secondary Outcome Measures (submitted: February 26, 2024)

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

Original Secondary Outcome Measures (submitted: July 20, 2021)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)
• 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)
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Nonalcoholic Steatohepatitis

Intervention

• Drug: Semaglutide (SEMA)
  Administered as subcutaneous (SC) injection
• Drug: Cilofexor (CILO)/Firsocostat (FIR)
  Tablets administered orally
  Other Name: GS-9674/GS-0976
• Drug: PTM SEMA
  Administered as SC injection
• Drug: PTM CILO/FIR
  Tablets administered orally

Study Arms

• 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
  Interventions:

  • Drug: Semaglutide (SEMA)
  • Drug: Cilofexor (CILO)/Firsocostat (FIR)
• 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
  Interventions:

  • Drug: Semaglutide (SEMA)
  • Drug: PTM CILO/FIR
• Experimental: PTM SEMA + CILO/FIR FDC
  PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks
  Interventions:

  • Drug: Cilofexor (CILO)/Firsocostat (FIR)
  • Drug: PTM SEMA
• Placebo Comparator: PTM SEMA + PTM CILO/FIR
  PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks
  Interventions:

  • Drug: PTM SEMA
  • Drug: PTM CILO/FIR

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 17, 2023): 457
• Original Estimated Enrollment (submitted: July 20, 2021): 440
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Japan, Puerto Rico, Spain, United States

Administrative Information

• NCT Number: NCT04971785
• Other Study ID Numbers: GS-US-454-6075; 2021-001445-12 ( EudraCT Number ); jRCT2071210112 ( Registry Identifier: jRCT )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gilead Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Gilead Sciences
• Original Study Sponsor: Same as current
• Collaborators: Novo Nordisk A/S

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: February 2024