A PHASE 2, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO-CONTROLLED, DOSE-RANGING, DOSE-FINDING, PARALLEL GROUP STUDY TO ASSESS EFFICACY AND SAFETY OF PF-06865571 (DGAT2I) ALONE AND WHEN COADMINISTERED WITH PF-05221304 (ACCI) IN ADULT PARTICIPANTS WITH BIOPSY-CONFIRMED NONALCOHOLIC STEATOHEPATITIS AND FIBROSIS STAGE 2 OR 3
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 256
- 试验地点
- 286
- 主要终点
- Mean Proportion of Participants Achieving Resolution of NASH Without Worsening/Improvement of Fibrosis by >=1 Stage Without Worsening of NASH/Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48:Bayesian Dose Response Model (BDRM)
研究概览
简要总结
The study aims to evaluate two, orally administered, investigational agents - PF-06865571 (DGAT2 inhibitor) and the coadministration of PF-06865571 with PF-05221304 (ACC inhibitor). This study is specifically designed to evaluate the effect of a range of doses of DGAT2i alone, and DGAT2i + ACCi, on resolution of NASH or improvement in liver fibrosis, as assessed histologically (via liver biopsy).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double blind, double dummy, placebo controlled
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
- •Biopsy proven NASH with either F2 or F3 fibrosis, per NASH CRN definition
- •BMI >/= 22.5kg/m2
排除标准
- •Evidence of other causes of liver disease such as Alcoholic steatohepatitis, (de)compensated cirrhosis, active viral hepatitis
- •Any condition possibly affecting drug absorption -Unstable concomitant medical conditions, based on medical history or screening laboratory results including-
- •unstable liver function tests, recent cardiovascular event(s) significant malignancies,
研究组 & 干预措施
Placebo
participants will receive medication for 48 weeks
干预措施: Placebo (Drug)
PF-06865571 25 milligrams (mg) twice daily (BID)
participants will receive medication for 48 weeks
干预措施: PF-06865571 (Drug)
PF-06865571 75 mg BID
participants will receive medication for 48 weeks
干预措施: PF-06865571 (Drug)
PF-06865571 150 mg BID
participants will receive medication for 48 weeks
干预措施: PF-06865571 (Drug)
PF-06865571 300 mg BID
participants will receive medication for 48 weeks
干预措施: PF-06865571 (Drug)
PF-06865571 (150 mg BID) + PF-05221304 (5 mg BID)
participants will receive medication for 48 weeks
干预措施: PF-06865571 (Drug)
PF-06865571 (150 mg BID) + PF-05221304 (5 mg BID)
participants will receive medication for 48 weeks
干预措施: PF-05221304 (Drug)
PF-06865771 (300 mg BID) + PF-05221304 (10 mg BID)
participants will receive medication for 48 weeks
干预措施: PF-06865571 (Drug)
PF-06865771 (300 mg BID) + PF-05221304 (10 mg BID)
participants will receive medication for 48 weeks
干预措施: PF-05221304 (Drug)
结局指标
主要结局
Mean Proportion of Participants Achieving Resolution of NASH Without Worsening/Improvement of Fibrosis by >=1 Stage Without Worsening of NASH/Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48:Bayesian Dose Response Model (BDRM)
时间窗: Week 48
NASH resolution: disappearance of ballooning (Nonalcoholic Fatty Liver Disease \[NAFLD\] Activity Score \[NAS\] ballooning score=0;0=no ballooning,1=few balloon cells,2=many cells with prominent ballooning; higher scores(HS)=more disease activity \[DA\]),residual/no lobular inflammation(NAS lobular inflammation score 0/1,0=no foci,1= \<2 foci, 2=2-4 foci,3= \>4 foci; HS=more DA),NAS steatosis score 0,1,2,3; 0= \<5% hepatocytes involved (HI),1=5-33% HI ,2= 34-66% HI, 3= \>66% HI; HS=more DA. No worsening of fibrosis: no change/decrease of at least 1 stage in Brunt-Kleiner scale (BKS) compared to baseline (CTB). Improvement in fibrosis by \>=1 stage: decrease of at least 1 stage in BKS CTB. No worsening of NASH: no change/increase in NAS for ballooning, inflammation, steatosis CTB. BDRM utilized to characterize dose response across BID treatment groups, estimate posterior mean proportion (\& 90% credible interval \[CI\], indicated as 'confidence interval' below) for placebo and each BID dose studied.
Number of Participants Achieving Resolution of NASH Without Worsening or Improvement in Fibrosis by >= 1 Stage Without Worsening of NASH or Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48: Logistic Regression Model
时间窗: Week 48
Resolution of NASH: disappearance of ballooning (NAS ballooning score= 0; where 0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity), residual or no lobular inflammation (NAS lobular inflammation score 0 or 1, where 0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), NAS steatosis score 0, 1, 2, or 3, where 0= \<5% hepatocytes involved, 1= 5-33% hepatocytes involved, 2= 34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores= more disease activity. No worsening of fibrosis: no change or decrease of at least 1 stage in BKS compared to baseline. Improvement in fibrosis by \>=1 stage: decrease of at least 1 stage in BKS compared to baseline. No worsening of NASH: no change or increase in NAS for ballooning, inflammation, steatosis compared to baseline.
次要结局
- Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model(Baseline, Week 48)
- Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA)(Baseline, Week 48)
- Mean Proportion of Participants Achieving Resolution of NASH, Without Worsening of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model(Week 48)
- Number of Participants Achieving Resolution of NASH, Without Worsening of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model(Week 48)
- Mean Proportion of Participants Achieving Improvement in Fibrosis by >=1 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model(Week 48)
- Number of Participants Achieving Improvement in Fibrosis by >=1 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model(Week 48)
- Mean Proportion of Participants Achieving Improvement in Fibrosis by >=2 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model(Week 48)
- Number of Participants Achieving Improvement in Fibrosis by >=2 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model(Week 48)
- Mean Proportion of Participants Achieving Improvement of >=2 Points in Total NAS, Without Progression of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model(Week 48)
- Number of Participants Achieving Improvement of >=2 Points in Total NAS Without Progression of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model(Week 48)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks))
- Number of Participants With Laboratory Test Abnormalities(From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks))
- Number of Participants With Clinically Significant Abnormalities in Vital Signs(From first dose of study drug (Day 1) upto Week 48 (maximum up to approximately 50 weeks))
- Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters(From first dose of study drug (Day 1) upto Week 48 (maximum up to approximately 50 weeks))