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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 457
- 试验地点
- 229
- 主要终点
- Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups
研究概览
简要总结
The goal of this clinical study is to understand whether the study drugs, semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR), cause fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with cirrhosis due to NASH.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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/1.73 m^2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
- •Hemoglobin A1c (HbA1c) ≤ 10%
- •International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation
- •Platelet count ≥ 125,000/µL
- •Alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)
- •Serum albumin ≥ 3.5 g/dL
- •Serum alkaline phosphatase (ALP) ≤ 2 x ULN
- •Body mass index (BMI) ≥ 23 kg/m^2 at screening.
排除标准
- •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 (SARS)-coronavirus 2 (CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) test.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
SEMA + CILO/FIR FDC
Participants will receive semaglutide (SEMA) 3.0 mg/mL, once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet, once daily up to 72 weeks.
干预措施: Semaglutide (SEMA) (Drug)
SEMA + CILO/FIR FDC
Participants will receive semaglutide (SEMA) 3.0 mg/mL, once weekly and cilofexor and firsocostat (CILO/FIR) 30 mg/20 mg fixed-dose combination (FDC) tablet, once daily up to 72 weeks.
干预措施: Cilofexor (CILO)/Firsocostat (FIR) (Drug)
SEMA + PTM CILO/FIR
Participants will receive SEMA 3.0 mg/mL, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet, once daily up to 72 weeks.
干预措施: Semaglutide (SEMA) (Drug)
SEMA + PTM CILO/FIR
Participants will receive SEMA 3.0 mg/mL, once weekly and Placebo-To-Match (PTM) CILO/FIR FDC tablet, once daily up to 72 weeks.
干预措施: PTM CILO/FIR (Drug)
PTM SEMA + CILO/FIR FDC
Participants will receive PTM SEMA, once weekly and CILO/FIR 30 mg/20 mg FDC tablet, once daily up to 72 weeks.
干预措施: Cilofexor (CILO)/Firsocostat (FIR) (Drug)
PTM SEMA + CILO/FIR FDC
Participants will receive PTM SEMA, once weekly and CILO/FIR 30 mg/20 mg FDC tablet, once daily up to 72 weeks.
干预措施: PTM SEMA (Drug)
PTM SEMA + PTM CILO/FIR
Participants will receive PTM SEMA, once weekly and PTM CILO/FIR FDC tablet, once daily up to 72 weeks.
干预措施: PTM SEMA (Drug)
PTM SEMA + PTM CILO/FIR
Participants will receive PTM SEMA, once weekly and PTM CILO/FIR FDC tablet, once daily up to 72 weeks.
干预措施: PTM CILO/FIR (Drug)
结局指标
主要结局
Percentage of Participants Who Achieved ≥ 1-Stage Improvement in Fibrosis Without Worsening of Nonalcoholic Steatohepatitis (NASH) at Week 72 in Semaglutide (SEMA) + Cilofexor/Firsocostat (CILO/FIR) Fixed Dose Combination (FDC) Versus Placebo Groups
时间窗: Week 72
Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. Clopper-Pearson method was used in outcome measure analysis in each arm. Percentages were rounded-off.
次要结局
- Percentage of Participants Who Achieved ≥1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 72 in SEMA + CILO/FIR FDC Versus SEMA Alone(Week 72)
- Percentage of Participants With NASH Resolution Without Worsening in Fibrosis at Week 72 in SEMA + CILO/FIR FDC Versus Placebo Groups(Week 72)
- Percentage of Participants With NASH Resolution Without Worsening in Fibrosis In Participants Treated With SEMA + CILO/FIR FDC Versus CILO/FIR Alone Groups(Week 72)