A Phase 3, Multinational, Double-Blind, Randomized, Placebo-Controlled Study of MGL-3196 (Resmetirom) in Patients With Non-Alcoholic Steatohepatitis (NASH) and Fibrosis to Resolve NASH and Reduce Progression to Cirrhosis and/or Hepatic Decompensation
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 1,759
- 试验地点
- 388
- 主要终点
- Week 52 Dual Primary Objectives: To determine the effect of 80 or 100 mg MGL-3196 vs matching placebo on liver biopsy (NASH CRN score) at Week 52 compared with Baseline
研究概览
简要总结
A double-blind placebo controlled randomized Phase 3 study to determine if 80 or 100 mg of MGL-3196 as compared with placebo resolves NASH and/or reduces fibrosis on liver biopsy and prevents progression to cirrhosis and/or advanced liver disease
详细描述
Primary and secondary endpoint population at Week 52 will be at least 900 patients, more than half fibrosis score 3 (F3), the remainder fibrosis score 2 (F2) and <10% fibrosis score F1B (F1B) based on final liver biopsy baseline fibrosis score.
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
- 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
- •Must be willing to participate in the study and provide written informed consent.
- •Male and female adults ≥ 18 years of age.
- •Suspected or confirmed diagnosis of NASH fibrosis suggested by the historical data. Meet one of the following criteria that is consistent with NASH liver fibrosis:
- •Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL or ELF ≥9
- •FibroScan with transient elastography ≥8.5 kPa and controlled attenuation parameter ≥280 dB.m-1
- •Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage.
- •MRI-PDFF fat fraction ≥8% obtained during the screening period
- •Biopsy-proven NASH (baseline liver biopsy) based on a liver biopsy obtained ≤6 months before anticipated date of randomization (if the biopsy is deemed acceptable for interpretation by the central reader) with fibrosis stage 1A/1C, 1B, 2, or 3 on liver biopsy and NAS of ≥4 with a score of at least 1 in each of the following NAS components:
- •Steatosis (scored 0 to 3)
- •Ballooning degeneration (scored 0 to 2)
- •Lobular inflammation (scored 0 to 3)
排除标准
- •History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening.
- •Regular use of drugs historically associated with NAFLD
- •Thyroid diseases:
- •Active hyperthyroidism.
- •Untreated clinical hypothyroidism defined by thyroid stimulating hormone (TSH) >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms.
- •Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 µg per day are allowed.
- •History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
- •Recent significant weight gain or loss
- •HbA1c ≥ 9.0%.
- •Glucagon-like peptide 1 [GLP-1] agonist, high dose Vitamin E (> 400 IU/day), or pioglitazone therapy unless stable dose for 24 weeks prior to biopsy.
- •Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
- •Diagnosis of hepatocellular carcinoma (HCC).
- •MELD score ≥12, as determined at Screening, unless due to therapeutic anti coagulation.
- •Hepatic decompensation
- •Chronic liver diseases other than NASH
- •Active autoimmune disease
- •Serum ALT > 250 U/L.
- •Active, serious medical disease with a likely life expectancy < 2 years.
- •Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer.
- •Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.
研究组 & 干预措施
80 mg MGL-3196
80 mg daily
干预措施: MGL-3196 (Drug)
100 mg MGL-3196
100 mg daily
干预措施: MGL-3196 (Drug)
100 mg MGL-3196
100 mg daily
干预措施: Liver Biopsy (Procedure)
Matching Placebo
Placebo Daily
干预措施: Placebo (Drug)
Matching Placebo
Placebo Daily
干预措施: Liver Biopsy (Procedure)
80 mg MGL-3196
80 mg daily
干预措施: Liver Biopsy (Procedure)
结局指标
主要结局
Week 52 Dual Primary Objectives: To determine the effect of 80 or 100 mg MGL-3196 vs matching placebo on liver biopsy (NASH CRN score) at Week 52 compared with Baseline
时间窗: 52 weeks
1. Proportion with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least 2-point reduction in NAFLD Activity Score (NAS) without worsening of fibrosis stage OR 2. Proportion with at least a 1-point improvement in fibrosis stage with no worsening of NAS
Month 54 Primary Objective: Time to experiencing an adjudicated Composite Clinical Outcome event (Final Primary Endpoint, at 54 months)
时间窗: up to 54 months
The Composite Clinical Outcome is composed of all-cause mortality, liver transplant, and significant hepatic events (including hepatic decompensation events \[ascites, encephalopathy, or gastroesophageal variceal hemorrhage\], histological progression to cirrhosis, and a confirmed increase of MELD score from \<12 to ≥15).
次要结局
- Week 52 Key Secondary Objective: To determine the effect of once-daily, oral administration of MGL-3196 80 or 100 mg versus matching placebo on the percent change from Baseline at 24 weeks in directly measured low-density lipoprotein cholesterol (LDL-C)(24 weeks)