Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
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DOI：
10.1016/s0140-6736(17)31611-2
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发表时间：
2017-09-23
期刊：
影响因子：
168.9
通讯作者：
Mercuri, Eugenio
中科院分区：
文献类型：
--
作者：
McDonald, Craig M.;Campbell, Craig;Mercuri, Eugenio
背景杜氏肌营养不良症（DMD）是一种严重的、进行性的、罕见的神经肌肉性X连锁隐性遗传疾病。肌营养不良蛋白缺乏症是疾病的根本原因;因此，正在探索旨在恢复肌营养不良蛋白蛋白生产的突变特异性疗法。我们的目的是评估阿他鲁仑的疗效和安全性，在门诊男孩无义突变DMD.Methods我们做了这个多中心，随机，双盲，安慰剂对照，3期试验在54个地点在18个国家位于北美，欧洲，亚太地区和拉丁美洲。无义突变DMD的7-16岁男孩，基线6分钟步行距离（6 MWD）为150米或更长，年龄和身高预测正常值的80%或更少，通过交互式语音应答或网络应答系统进行排列区组随机化（区组大小为4），随机分配（1：1）接受阿他鲁伦口服每日3次（40 mg/kg/天）或匹配的安慰剂。按年龄（≥ 9岁）、既往皮质类固醇使用持续时间（6个月至≥ 12个月）和基线6 MWD（≥ 350个月）对随机化进行分层。患者、父母和护理人员、研究中心工作人员、PTC Therapeutics员工和所有其他研究工作人员均对分组设盲，直至数据库锁定后。主要终点为第48周6 MWD较基线的变化。我们还根据基线6 MWD对主要终点进行了预先指定的亚组分析，6 MWD反映了1年内疾病进展的预期率。主要分析是通过意向治疗进行的，该研究已在ClinicalTrials注册。结果在2013年3月26日至2014年8月26日期间，我们随机分配了230名患者接受阿他仑（n=115）或安慰剂（n =115）; 228名患者组成意向治疗人群。阿他鲁仑治疗患者从基线至第48周6 MWD的最小二乘平均变化为-47.7 m（SE 9.3），安慰剂治疗患者为-60.7 m（9.3）（差异13.0 m [SE 10.4]，95% CI -7.4至33.4; p=0.213）。在预先指定的亚组中，阿他鲁伦与安慰剂相比的最小二乘平均变化为-7.7 m（SE 24.1，95% CI -54.9至39.5; p=0.749）6 MWD小于300 m的组，42.9 m（15.9，11.8-74.0; p=0.007），在6 MWD为300 m或更高至小于400 m的组中，和-9.5 m（17.2，-43.2至24.2; p=0.580），在6 MWD为400 m或更高的组中。Ataluren通常耐受良好，大多数治疗后出现的不良事件的严重程度为轻度至中度。8例（3%）患者（每组n=4）报告了严重不良事件;安慰剂组中除1起事件外的所有事件（肝功能异常被认为可能与治疗有关）被认为与治疗无关。阿他卢仑组和安慰剂组患者之间6 MWD的解释变化没有显著差异，无论是在意向治疗人群中，还是在基线6 MWD小于300 m或400 m或更大的预先指定亚组中。然而，我们记录了阿他卢仑在基线6 MWD为300 m或以上至小于400 m的预先指定的患者亚组中的显著效果。在此范围内的基线6 MWD值与1年内更可预测的下降率相关;这一发现对未来以6分钟步行试验为终点的DMD试验的设计具有影响。
Background Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD.Methods We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (= 9 years), duration of previous corticosteroid use (6 months to = 12 months), and baseline 6MWD (= 350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials. gov, number NCT01826487.Findings Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47.7 m (SE 9.3) for ataluren-treated patients and -60.7 m (9.3) for placebo-treated patients (difference 13.0 m [SE 10.4], 95% CI -7.4 to 33.4; p=0.213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7.7 m (SE 24.1, 95% CI -54.9 to 39.5; p=0.749) in the group with a 6MWD of less than 300 m, 42.9 m (15.9, 11.8-74.0; p=0.007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9.5 m (17.2, -43.2 to 24.2; p=0.580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment.Interpretation Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint.