NCT02217475已完成2 期
CENTAUR: Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Subjects With Liver Fibrosis
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 289
- 主要终点
- Number of Participant With Hepatic Histological Improvement in NAS by ≥ 2 Points With at Least 1-Point Reduction in Either Lobular Inflammation or Hepatocellular Ballooning and no Concurrent Worsening of Fibrosis at Year 1
研究概览
简要总结
The purpose of this study is to determine whether cenicriviroc is effective and safe in the treatment of nonalcoholic steatohepatitis (NASH) in adult participants with liver fibrosis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult participants aged between 18-75
- •Histological evidence of NASH, based on biopsy, with a Nonalcoholic fatty liver disease Activity Score (NAS) of >= 4 with at least 1 in each component of NAS
- •Histological evidence of liver fibrosis defined as NASH Clinical Research Network (CRN) System Stage 1 to 3
- •Meeting any of the 3 major criteria (a, b, c):
- •Documented evidence of type 2 diabetes mellitus
- •High body mass index (> 25 kg/m^2) with at least one of the following criteria of metabolic syndrome, as defined by the National Cholesterol Education Program:
- •Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 35 inches (female)
- •Dyslipidemia: Triglycerides ≥ 1.7 mmol/L (150 mg/dL)
- •Dyslipidemia: High-density lipoprotein (HDL)-cholesterol < 40 mg/dL (male), < 50 mg/dL (female)
- •Blood pressure ≥ 130/85 mmHg (or currently being treated for hypertension)
- •Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL)
- •Bridging fibrosis (NASH CRN Stage 3) and/or definite NASH (NAS ≥ 5)
- •Agree to have one liver biopsy at Screening, one at Year 1, and one at the end of study treatment (Year 2)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × upper limit of normal (ULN)
排除标准
- •Hepatitis B surface Antigen (HBsAg) positive
- •Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:
- •Participants previously treated for viral hepatitis C with at least a 1-year period since documented sustained virologic response at Week 12 (post-treatment) may be eligible if all other eligibility criteria are met
- •Participants with presence of hepatitis C antibody but negative hepatitis C virus ribonucleic acid RNA without treatment (i.e., spontaneous clearance) may be eligible if all other eligibility criteria are met
- •Prior or planned liver transplantation
- •Other known causes of chronic liver disease, including alcoholic liver disease
- •History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding
- •Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits [25 mL] or 1 glass of wine [125 mL])
- •Human immunodeficiency virus (HIV)-1 or HIV-2 infection
- •Weight reduction through bariatric surgery in the past 5 years or planned during the conduct of the study (including gastric banding)
- •Females who are pregnant or breastfeeding
- •Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study or unable to comply with the dosing and protocol requirements.
研究组 & 干预措施
Cenicriviroc (CVC) 150mg/CVC 150 mg
Experimental
CVC 150 mg tablet in Years 1 and 2.
干预措施: Cenicriviroc (Drug)
Placebo/CVC 150 mg
Experimental
Placebo-matching CVC tablet in Year 1 then CVC 150 mg tablet in Year 2.
干预措施: Cenicriviroc (Drug)
Placebo/CVC 150 mg
Experimental
Placebo-matching CVC tablet in Year 1 then CVC 150 mg tablet in Year 2.
干预措施: Placebo (Drug)
Placebo/Placebo
Placebo Comparator
Placebo-matching cenicriviroc (CVC) tablet in Years 1 and 2.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participant With Hepatic Histological Improvement in NAS by ≥ 2 Points With at Least 1-Point Reduction in Either Lobular Inflammation or Hepatocellular Ballooning and no Concurrent Worsening of Fibrosis at Year 1
时间窗: Year 1
Hepatic histological improvement in Nonalcoholic Fatty Liver Disease Activity Score (NAS) at Year 1 was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Evaluation of fibrosis stage was based on the nonalcoholic steatohepatitis clinical research network (NASH CRN) fibrosis staging system, which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. Worsening of fibrosis stage was defined as progression of NASH CRN fibrosis stage.
次要结局
- Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 1(Year 1)
- Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage and Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2(Year 2)
- Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 2(Year 2)
- Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 1(Baseline (Day 1) to Year 1)
- Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 2(Baseline (Day 1) to Year 2)
- Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage and Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1(Year 1)
- Number of Participants With Clinically Abnormal in Electrocardiogram (ECG) Findings(Years 1 and 2)
- Number of Participants With Hepatic Histological Improvement in NAS at Year 2(Year 2)
- Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 1(Year 1)
- Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 2(Year 2)
- Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1(Year 1)
- Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2(Year 2)
- Number of Participants With Deaths, Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading Study Drug to Discontinuation(Years 1 and 2)
- Number of Participants With Clinically Significant Changes in Vital Signs(Years 1 and 2)
- Number of Participants With Clinical Laboratory Abnormalities(Years 1 and 2)
- Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 2(Year 2)
- Number of Participants With Hepatic Histological Improvement With a Minimum 2-Point Improvement in NAS With at Least a 1-Point Improvement in More Than 1 Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 1(Year 1)
- Number of Participants With Hepatic Histological Improvement With a Minimum 2-Point Improvement in NAS With at Least a 1-point Improvement in More Than 1 Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 2(Year 2)
- Number of Participants With Resolution of NASH Using a Modified Definition Based on Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 1(Year 1)
- Number of Participants With Resolution of NASH Using a Modified Definition Based on Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 2(Year 2)
- Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 1(Year 1)
- Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 1(Year 1)
- Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 2(Year 2)
- Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 1(Baseline (Day 1) to Year 1)
- Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 2(Baseline (Day 1) to Year 2)
- Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 1(Baseline (Day 1) to Year 1)
- Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 2(Baseline (Day 1) to Year 2)
- Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 3, 6 and 12(Baseline (Month 0) to Months 3, 6 and 12)
- Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 15, 18 and 24(Baseline (Month 0) to Months 15, 18 and 24)
- Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 3, 6 and 12(Baseline (Month 0) to Months 3, 6 and 12)
- Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 15, 18 and 24(Baseline (Month 0) to Months 15, 18 and 24)
- Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 6 and 12(Baseline (Month 0) to Months 6 and 12)
- Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 18 and 24(Baseline (Month 0) to Months 18 and 24)
- Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS) at Months 3, 6 and 12(Baseline (Month 0) to Months 3, 6 and 12)
- Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: NAFLD Fibrosis Score (NFS) at Months 15, 18 and 24(Baseline (Month 0) to Months 15, 18 and 24)
- Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 6 and 12(Baseline (Month 0) to Months 6 and 12)
- Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 18 and 24(Baseline (Month 0) to Months 18 and 24)
- Change From Baseline in Biomarkers of Hepatocyte Apoptosis: Caspase Cleaved (CK-18 [M-30]) Levels and Total M-65 (CK-18 [M-65]) Levels at Months 3, 6 and 12(Baseline (Month 0) to Months 3, 6 and 12)
- Change From Baseline in Biomarkers of Hepatocyte Apoptosis: Caspase Cleaved (CK-18 [M-30]) Levels and Total M-65 (CK-18 [M-65]) Levels at Months 15, 18 and 24(Baseline (Month 0) to Months 15, 18 and 24)
- Change From Baseline in Weight at Months 3, 6 and 12(Baseline (Day 1) to Months 3, 6 and 12)
- Change From Baseline in Weight at Months 15, 18 and 24(Baseline (Day 1) to Months 15, 18 and 24)
- Change From Baseline in Body Mass Index (BMI) at Months 3, 6 and 12(Baseline (Day 1) to Months 3, 6 and 12)
- Change From Baseline in Body Mass Index (BMI) at Months 15, 18 and 24(Baseline (Day 1) to Months 15, 18 and 24)
- Change From Baseline in Waist Circumference at Months 3, 6 and 12(Baseline (Day 1) to Months 3, 6 and 12)
- Change From Baseline in Waist Circumference at Months 15, 18 and 24(Baseline (Day 1) to Months 15, 18 and 24)
- Change From Baseline in Hip Circumference at Months 3, 6 and 12(Baseline (Day 1) to Months 3, 6 and 12)
- Change From Baseline in Hip Circumference at Months 15, 18 and 24(Baseline (Day 1) to Months 15, 18 and 24)
- Change From Baseline in Forearm Circumference at Months 3, 6 and 12(Baseline (Day 1) to Months 3, 6 and 12)
- Change From Baseline in Forearm Circumference at Months 15, 18 and 24(Baseline (Day 1) to Months 15, 18 and 24)
- Change From Baseline in Tricep Skinfold Thickness at Months 3, 6 and 12(Baseline (Day 1) to Months 3, 6 and 12)
- Change From Baseline in Tricep Skinfold Thickness at Months 15, 18 and 24(Baseline (Day 1) to Months 15, 18 and 24)
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