Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial
Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial
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DOI：
10.1016/s1474-4422(19)30200-5
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发表时间：
2019-09-01
期刊：
影响因子：
48
通讯作者：
Nishino, Ichizo
中科院分区：
文献类型：
--
作者：
Hanna, Michael G.;Badrising, Umesh A.;Nishino, Ichizo
背景包涵体肌炎是一种特发性炎症性肌病，是50岁以上人群最常见的肌病。迄今为止，还没有有效的药物治疗。我们的目的是评估bimagrumab的安全性，有效性和耐受性，一个完全人的单克隆抗体，在个人与包涵体myositive.Methods我们做了一个多中心，双盲，安慰剂对照研究（RESILIENT）在38个学术临床网站在澳大利亚，欧洲，日本和美国。如果个体（年龄36 - 85岁）符合2010年医学研究理事会修订的包涵体肌炎标准，则有资格参加本研究。我们使用区组随机化方案（区组大小为4）将受试者（1：1：1：1）随机分配至bimagrumab（10 mg/kg、3 mg/kg或1 mg/kg）或与bimagrumab外观匹配的安慰剂组，每4周一次静脉输注给药，持续至少48周。所有研究参与者、资助者、研究者、研究中心工作人员和进行评估的人员均对治疗分配设盲。主要结局指标为6分钟步行距离（6 MWD），在主要分析人群中于第52周进行评估，并按意向治疗原则进行分析。我们使用多变量正态重复测量模型来分析6 MWD的数据。通过记录不良事件以及心电图、超声心动图、血液学检查、尿分析和血生化来评估安全性。本试验注册于ClinicalTrials.gov，注册号为NCT 01925209;本报告为最终分析结果。结果2013年9月26日至2016年1月6日期间，共有251名受试者入组本研究，其中63名被分配至各bimagrumab组，62名被分配至安慰剂组。第52周时，任何bimagrumab剂量与安慰剂之间的6 MWD较基线的变化均无差异（bimagrumab 10 mg/kg组的最小二乘平均治疗差异，17.6 m，SE 14.3，99% CI -19.6至54.8; p=0.22; 3 mg/kg组，18.6 m，14.2，-18.2至55.4; p=0.19; 1 mg/kg组，1.3 m，14.1，-38.0至35.4; p=0.93）。每个bimagrumab组中有63名（100%）参与者，安慰剂组62名参与者中有61名（98%）至少发生过一次不良事件。福尔斯是最常见的不良事件（bimagrumab 10 mg/kg组48例[76%]，3 mg/kg组55例[87%]，1 mg/kg组54例[86%]，安慰剂组52例[84%]）。bimagrumab最常报告的不良事件是肌肉痉挛（bimagrumab 10 mg/kg组32 [51%]，3 mg/kg组43 [68%]，1 mg/kg组25 [40%]，安慰剂组13 [21%]）和腹泻（分别为33 [52%]、28 [44%]、20 [32%]和11 [18%]）。每个bimagrumab组有4名（6%）参与者报告了导致停药的不良事件，而安慰剂组有1名（2%）参与者。10 mg/kg组21例（33%）受试者、3 mg/kg组11例（17%）受试者、1 mg/kg组20例（32%）受试者和安慰剂组20例（32%）受试者报告了至少1起严重不良事件。心电图或超声心动图未记录到显著的心脏不良反应。研究期间报告了两例死亡，一例归因于心内膜下心肌梗死（故意过量服用镇静剂和抗抑郁药后继发于胃肠道出血），一例归因于肺腺癌。研究者认为这两例死亡均与bimagrumab有关。解释在患有包涵体肌炎的个体中，相对于安慰剂，Bimagrumab显示出良好的安全性特征，但不改善6 MWD。我们研究的优势在于，据我们所知，这是在包涵体肌炎患者中进行的最大规模的随机对照试验，它提供了超过12个月的重要自然史数据。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis.Methods We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 3685 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis.Findings Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17.6 m, SE 14.3, 99% CI -19.6 to 54.8; p=0.22; for 3 mg/kg group, 18.6 m, 14.2, -18.2 to 55.4; p=0.19; and for 1 mg/kg group, 1.3 m, 14.1, -38.0 to 35.4; p=0.93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab.Interpretation Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. Copyright (C) 2019 Elsevier Ltd. All rights reserved.