Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy
Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy
复制标题
DOI：
10.1056/nejmoa1702752
复制
发表时间：
2017-11-02
影响因子：
158.5
通讯作者：
De Vivo, D. C.
中科院分区：
文献类型：
--
作者：
Finkel, R. S.;Mercuri, E.;De Vivo, D. C.
背景&帕拉;&帕拉;脊髓性肌萎缩症是一种常染色体隐性遗传性神经肌肉疾病，是由运动神经元存活蛋白（SMN）水平不足引起的。Nusinersen是一种反义寡核苷酸药物，可以修饰SMN 2基因的前信使RNA剪接，从而促进全长SMN蛋白的产生。帕拉;&帕拉;方法和帕拉;&帕拉;我们在患有脊髓性肌萎缩症的婴儿中进行了一项nusinersen的随机化、双盲、假手术对照、III期疗效和安全性试验。主要终点是运动里程碑反应（根据Hammersmith婴儿神经学检查结果定义）和无事件生存期（至死亡或使用永久辅助通气的时间）。次要终点包括根据筛选时疾病持续时间对所有生存期和无事件生存期的亚组分析。在预先规定的中期分析中，仅检验了第一个主要终点。为了将总体I类错误率控制在0.05，在最终分析中对第二个主要终点和次要终点使用分层检验策略。帕拉;&帕拉;结果&帕拉;&帕拉;在中期分析中，诺西那生组中出现运动里程碑反应的婴儿百分比显著高于对照组（21/51例婴儿[41%] vs. 0/27例[0%]，P
BACKGROUND & para;& para;Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.& para;& para;METHODS & para;& para;We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included over all survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.& para;& para;RESULTS & para;& para;In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41 %] vs. 0 of 27 [0%], P