NCT07221227招募中3 期
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study to Investigate the Safety and Efficacy of Efimosfermin Alfa in Participants With Biopsy-Confirmed F2- or F3-Stage Metabolic Dysfunction-Associated Steatohepatitis (MASH) (ZENITH-1)
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,200
- 试验地点
- 90
- 主要终点
- Time from randomization to an adjudicated composite liver-related clinical outcome
研究概览
简要总结
The purpose of this study is to assess the safety and efficacy of efimosfermin alfa in the resolution of steatohepatitis and improvement of liver-related clinical outcome compared to placebo in individuals with MASH and biopsy-confirmed F2- or F3-stage fibrosis.
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)
盲法说明
This is a double blind study.
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
- •Able and willing to understand and sign a written informed consent form that must be obtained prior to the initiation of study procedures
- •Age >=18 and <=75 years at enrollment
- •History or presence of 2 or more of the 5 components of metabolic syndrome per American Heart Association definition
- •Liver biopsy confirmation of MASH consistent with stage F2 or F3 fibrosis and a NAS score >=4 confirmed by a central pathologist
排除标准
- •Contraindication or ineligibility for percutaneous liver biopsy
- •ALT or AST >=5 x upper limit of normal (ULN)
- •Total bilirubin >=1.3 milligram per deciliter (mg/dL). Individuals with documented Gilbert's syndrome may be enrolled if they experienced an isolated increase in total bilirubin of >=1.3 mg/dL and direct bilirubin is <=20% of total bilirubin; otherwise, the individual will be excluded.
- •Serum albumin <=3.5 grams per deciliter (g/dL)
- •International normalized ratio (INR) >=1.3 not due to therapeutic anticoagulation. Individuals receiving chronic anticoagulant treatment with higher INR values may be enrolled at the discretion of the Investigator and Study Medical Monitor.
- •Alkaline phosphatase (ALP) >=2*ULN
- •Platelet (PLT) count <140,000 per (/) cubic millimeter (mm^3); individuals with a PLT count between 110,000/mm^3 and 140,000/mm^3 may be enrolled after discussion with the Study Medical Monitor.
- •Serum creatinine >=1.5 mg/dL or creatinine clearance <=60 milliliter (mL)/minute (min)/1.73 square meter by Chronic Kidney Disease Epidemiology Collaboration equation
- •Alpha-fetoprotein >=20 nanogram per milliliter (ng/mL)
- •Glycated hemoglobin >=9.0%
- •Model for End-Stage Liver Disease score >=12 unless the score is elevated in the absence of liver dysfunction (e.g., Gilbert's syndrome)
- •Phosphatidyl ethanol (PEth) >=80 ng/mL at Screening
- •Evidence of infection with any of the following:
- •Human immunodeficiency virus;
- •Hepatitis B virus (detectable HBsAg at Screening);
- •Hepatitis C virus (HCV);
- •Chronic liver disease from any other cause including, but not limited to, alcoholic liver disease; evidence of portal hypertension; viral hepatitis or any history or evidence of cirrhosis on screening liver biopsy; or decompensated liver disease such as clinical ascites, bleeding gastroesophageal varices, hepatorenal syndrome, or hepatic encephalopathy prior to Screening or Day
- •Current or history of excessive alcohol intake for >=3 months within the 12-month period prior to Screening
研究组 & 干预措施
Participants receiving Placebo
Placebo Comparator
干预措施: Placebo (Drug)
Participants receiving dose level 1 of efimosfermin alfa
Experimental
干预措施: Efimosfermin alfa (Drug)
Participants receiving dose level 2 of efimosfermin alfa
Experimental
干预措施: Efimosfermin alfa (Drug)
结局指标
主要结局
Time from randomization to an adjudicated composite liver-related clinical outcome
时间窗: From Randomization (Day 1) to 48 months
Liver-related outcome will comprised of all-cause mortality; transplantation; occurrence of significant hepatic events.
Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of steatohepatitis at Week 52
时间窗: At Week 52
Proportion of participants experiencing improvement in fibrosis of greater than or equal to (\>=) 1 stage by MASH clinical research network (CRN) fibrosis scores and no worsening of steatohepatitis (defined as no increase in nonalcoholic fatty liver disease activity score \[NAS\] for ballooning, inflammation, or steatosis) at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity.
Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN fibrosis score at Week 52
时间窗: At Week 52
Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. NAS score ranges from 0 to 8, higher score indicates worse disease activity. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity.
次要结局
- Percent change from Baseline in VCTE-LSM(Baseline (Day 1), Week 52 and Month 48)
- Percent change from Baseline in CAP scores(Baseline (Day 1), Week 52 and Month 48)
- Percent change from Baseline in MRE Score(Baseline (Day 1), Week 52 and Month 48)
- Percent change from Baseline in ELF Score(Baseline (Day 1), Week 52 and Month 48)
- Percent change from Baseline in HFF by MRI-PDFF(Baseline (Day 1), Week 52 and Month 48)
- Percent change from Baseline in ALT and AST (International units per liter)(Baseline (Day 1), Week 52 and Month 48)
- Percent change from Baseline in ALT and AST ratio (ALT/AST)(Baseline (Day 1), Week 52 and Month 48)
- Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity(At Week 52 and at Month 48)
- Absolute change from Baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (International units per liter)(Baseline (Day 1), Week 52 and Month 48)
- Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity(At Week 52 and at Month 48)
- Number of participants with Grade 3 and Grade 4 laboratory abnormalities(At Week 52 and at Month 48)
- Proportion of participants experiencing resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >=1 stage at Week 52(At Week 52)
- Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of Steatohepatitis at Month 48(At Month 48)
- Proportion of participants experiencing improvement in fibrosis by >=2 stage and no worsening of Steatohepatitis at Week 52 and Month 48(At Week 52 and Month 48)
- Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN score at Month 48(At Month 48)
- Absolute change from Baseline in vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM)(Baseline (Day 1), Week 52 and Month 48)
- Percent Change from Baseline in VCTE-LSM(Baseline (Day 1), Week 52 and Month 48)
- Absolute change from Baseline in controlled attenuation parameter (CAP) scores(Baseline (Day 1), Week 52 and Month 48)
- Proportion of participants achieving Change from Baseline in VCTE-LSM >=30 percent (%) at Week 52 and Month 48(Baseline (Day 1), Week 52 and Month 48)
- Proportion of participants experiencing improvement in ELF score of >=0.5(At Week 52 and Month 48)
- Absolute change from Baseline in hepatic fat fraction (HFF) by MRI-derived proton density fat fraction (PDFF)(Baseline (Day 1), Week 52 and Month 48)
- Percent Change from Baseline in HFF by MRI-PDFF(Baseline (Day 1), Week 52 and Month 48)
- Percent Change from Baseline in ALT and AST (International units per liter)(Baseline (Day 1), Week 52 and Month 48)
- Absolute change from Baseline in ALT and AST ratio (ALT/AST)(Baseline (Day 1), Week 52 and Month 48)
- Percent Change from Baseline in ALT and AST ratio (ALT/AST)(Baseline (Day 1), Week 52 and Month 48)
- Proportion of participants experiencing ALT and HFF normalization at Week 52 and Month 48(At Week 52 and Month 48)
- Percent Change from Baseline in CAP scores(Baseline (Day 1), Week 52 and Month 48)
- Absolute change from Baseline in magnetic resonance elastography (MRE) scores(Baseline (Day 1), Week 52 and Month 48)
- Percent Change from Baseline in MRE Score(Baseline (Day 1), Week 52 and Month 48)
- Absolute change from Baseline in Enhanced Liver Fibrosis (ELF) Score(Baseline (Day 1), Week 52 and Month 48)
- Percent Change from Baseline in ELF Score(Baseline (Day 1), Week 52 and Month 48)
- Proportion of participants experiencing HFF <=5% at Week 52 and Month 48(At Week 52 and Month 48)
- Change from Baseline in glycated hemoglobin (HbA1c) (Percentage of HbA1c) in participants with Type 2 Diabetes Mellitus (T2DM)(Baseline (Day 1), Week 52 and Month 48)
- Change from Baseline in body weight (kilograms)(Baseline (Day 1), Week 52 and Month 48)
- Change from Baseline in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)- cholesterol, and triglycerides (Millimoles per liter)(Baseline (Day 1), Week 52 and Month 48)
- Proportion of participants with antidrug and antiFGF21 antibody (ADA)(At Week 52 and Month 48)
- Change from Baseline in Chronic Liver Disease Questionnaire-Nonalcoholic Steatohepatitis (CLDQ-NASH) in domain and total score(Baseline (Day 1), Week 52 and Month 48)
- Change from Baseline in Short Form-36 (SF-36) component and domain scores at Week 52 and Month 48(Baseline (Day 1), Week 52 and Month 48)
- Serum drug Concentration of efimosfermin alfa(Up to Month 48)
- Maximum serum drug concentration (Cmax) of efimosfermin alfa(Up to Month 48)
- Area under the serum concentration-time curve (AUC) of efimosfermin alfa(Up to Month 48)
- Average serum drug concentration (Cavg) of efimosfermin alfa(Up to Month 48)
- Serum concentration of study drug at the end of the dosing interval (Ctrough) of efimosfermin alfa(Up to Month 48)
- Exposure-response relationship for efimosfermin alfa(Baseline (Day 1), Week 52 and Month 48)
研究者
研究点 (90)
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