A Randomized, Double-blind, Parallel-group, Multicenter Study to Assess Efficacy, Safety, and Tolerability of Oral Tropifexor (LJN452) & Licogliflozin (LIK066) Combination Therapy and Each Monotherapy, Compared With Placebo for Treatment of Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis.(ELIVATE)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 234
- 试验地点
- 30
- 主要终点
- Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis
研究概览
简要总结
Randomized, double-blind, parallel-group, multicenter study to assess efficacy, safety, and tolerability of oral tropifexor & licogliflozin combination therapy and each monotherapy, compared with placebo for treatment of adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.
详细描述
The study consisted of 1) a screening period, 2) a treatment period starting from randomization on Day 0 and running to Week 48, and 3) a follow-up period of 4 weeks after the last dose of study treatment. The study duration from first dose of study medication was 52 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Presence of NASH with fibrosis confirmed by central reader's evaluation of liver biopsy obtained no more than 6 months before randomization as demonstrated by the following:
- •NASH using NAFLD Activity Score (NAS) ≥ 4 with at least 1 point each in inflammation and ballooning and
- •Fibrosis stage 2 or 3 using NASH CRN fibrosis criteria
排除标准
- •Type 1 diabetes mellitus
- •Uncontrolled type 2 diabetes defined as glycated hemoglobin (HbA1c) ≥ 9.0% at screening
- •HbA1c < 6.5% at screening in Type 2 diabetics currently treated with insulin or sulfonylureas
- •Clinical evidence of liver impairment as defined by the presence of any of the following abnormalities:
- •Platelet count < LLN (see Central laboratory manual).
- •Serum albumin < LLN (see Central laboratory manual).
- •International Normalized Ratio (INR) > ULN (see Central laboratory manual).
- •ALT or AST > 5× ULN (confirmed by 2 values during screening).
- •Total bilirubin > ULN (see Central laboratory manual) (confirmed by 2 values during screening), including Gilbert's syndrome.
- •Alkaline phosphatase > 300 IU/L (confirmed by 2 values during screening).
- •History of esophageal varices, ascites or hepatic encephalopathy
- •Splenomegaly
- •MELD score >12
研究组 & 干预措施
Arm D: Placebo
Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily
干预措施: Placebo (Other)
Arm A: combination therapy
Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally
干预措施: Tropifexor (Drug)
Arm A: combination therapy
Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally
干预措施: Licogliflozin (Drug)
Arm B: tropifexor monotherapy
Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally
干预措施: Tropifexor (Drug)
Arm C: licogliflozin monotherapy
Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally
干预措施: Licogliflozin (Drug)
结局指标
主要结局
Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis
时间窗: 48 weeks
Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline
时间窗: Baseline, Week 48
Response was defined as at least a one-stage improvement in fibrosis without worsening of nonalcoholic steatohepatitis (NASH) Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis.
次要结局
- Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH(48 weeks)
- Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH(48 weeks)
- Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis(48 weeks)
- Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline(Baseline, Week 48)
- Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF)(Baseline, Week 48)
- Change From Baseline in Alanine Transaminase (ALT) Over Time(Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks))
- Change From Baseline in Aspartate Aminotransferase (AST) Over Time(Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks))
- Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time(Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks))