Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
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DOI：
10.1016/s0140-6736(19)32517-6
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发表时间：
2019-11-30
期刊：
影响因子：
168.9
通讯作者：
Moussa, Sam E.
中科院分区：
文献类型：
--
作者：
Harrison, Stephen A.;Bashir, Mustafa R.;Moussa, Sam E.
背景：非酒精性脂肪性肝炎（NASH）以肝脂肪变性、炎症、肝细胞损伤和进行性肝纤维化为特征。Resmetirom （MGL-3196）是一种肝脏导向、口服活性、选择性甲状腺激素受体- β激动剂，旨在通过增加肝脏脂肪代谢和降低脂肪毒性来改善NASH。我们的目的是评估雷美替罗治疗NASH患者的安全性和有效性。MGL-3196-05是一项在美国25个中心进行的为期36周的随机、双盲、安慰剂对照研究。活检证实NASH（纤维化1-3期）的成年人，在mri质子密度脂肪分数（MRI-PDFF）评估时，肝脏脂肪分数在基线时至少为10%，符合条件。患者被计算机系统随机分配为2:1，接受雷司美替80毫克或相匹配的安慰剂，每天口服一次。在第12周和第36周进行了一系列肝脏脂肪测量，并在第36周进行了第二次肝脏活检。主要终点是在基线和第12周MRI-PDFF患者中，与安慰剂相比，第12周MRI-PDFF评估的肝脂肪的相对变化。该试验已在ClinicalTrials.gov注册，编号NCT02912260。研究结果：在美国的18个地点，筛选了348名患者，其中84名随机分配到雷司替罗组，41名随机分配到安慰剂组。雷司替龙治疗的患者（n=78）在第12周与安慰剂（n=38）相比，肝脂肪相对减少(雷司替龙治疗组为-32.9% vs安慰剂组为-10.4%；最小二乘平均差为-22.5%，95% CI为-32.9 ~ -12.2
Background Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-beta agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH.Methods MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260.Findings 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32.9% resmetirom vs -10.4% placebo; least squares mean difference -22.5%, 95% CI -32.9 to -12.2; p