Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial
Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial
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DOI：
10.1016/s1474-4422(13)70221-7
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发表时间：
2013-11-01
期刊：
影响因子：
48
通讯作者：
Kerr, Douglas A.
中科院分区：
文献类型：
--
作者：
Cudkowicz, Merit E.;van den Berg, Leonard H.;Kerr, Douglas A.
背景在一项2期研究中，右旋普拉克索（25-150 mg，每日两次）耐受性良好，长达9个月，并在肌萎缩侧索硬化症患者的功能和死亡率综合评估中显示出高剂量的显著益处。我们的目的是评估dexpramipexole的疗效和安全性在3期临床试验的患者与家族性或散发性diseases.Methods在我们的随机，双盲，安慰剂对照的3期试验（EMPOWER），我们招募的参与者年龄在18-80岁（首次肌萎缩侧索硬化症症状发作24个月或更少的基线前）在81个学术医疗中心在11个国家。我们通过集中式语音交互在线系统将合格参与者（1：1）随机分配至每日两次右旋普拉克索150 mg或匹配的安慰剂组，持续12-18个月，按试验中心、疾病发作区域（延髓vs其他区域）和既往使用利鲁唑进行分层。主要终点是功能和生存联合评估（CAFS）评分，基于肌萎缩侧索硬化症功能评定量表修订版（ALSFRS-R）总评分的变化和至死亡时间长达12个月。我们评估了所有至少接受一次剂量并且至少有一次剂量后ALSFRS-R测量或死亡的参与者的主要终点。我们监测了所有参与者的不良事件。该研究注册于ClinicalTrials.gov，编号NCT 01281189。结果在2011年3月28日至2011年9月30日期间，我们招募了943名参与者（474名随机分配的右旋普拉克索，468名随机分配的安慰剂，1名退出）。12个月时，右普拉克索组（评分441-76，95% CI 415.43-468.08）和安慰剂组（438.84，412.81-464.88; p=0.86）受试者的最小二乘平均CAFS评分无差异。在12个月时，我们注意到ALSFRS-R总评分（右普拉克索组为-13.34 vs安慰剂组为-13-42; p=0.90）或至死亡时间（74 [16%] vs 79 [17%];风险比1.03 [0.75-1.43]; p=0.84）较基线的平均变化无差异。右普拉克索组中37名（8%）参与者与安慰剂组中8名（2%）参与者相比发生了中性粒细胞减少症，并且组间其他不良事件的发生率相似。我们的试验可以为肌萎缩侧索硬化症未来临床研究策略的设计提供信息。
Background In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease.Methods In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189.Findings Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441-76, 95% CI 415.43-468.08) and those in the placebo group (438.84, 412.81-464.88; p=0.86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13.34 in the dexpramipexole group vs -13-42 in the placebo group; p=0.90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1.03 [0.75-1.43]; p=0.84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups.Interpretation Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis.