Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.
Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.
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锂与Riluzole结合治疗肌萎缩性侧面硬化症的安全性和功效：一项随机，双盲，安慰剂对照试验。
DOI：
10.1016/s1474-4422(10)70068-5
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发表时间：
2010-05
期刊：
影响因子：
48
通讯作者：
Cudkowicz, Merit
中科院分区：
文献类型：
--
作者：
Aggarwal, Swati P.;Zinman, Lorne;Simpson, Elizabeth;McKinley, Jane;Jackson, Katherine E.;Pinto, Hanika;Kaufman, Petra;Conwit, Robin A.;Schoenfeld, David;Shefner, Jeremy;Cudkowicz, Merit
我们研究了锂联合利鲁唑治疗ALS的安全性和有效性。最近，一项初步研究表明锂在减缓ALS进展方面具有显着作用。为了证实或反驳这些发现，美国和加拿大的资助组织和研究人员合作，以快速有效的方式设计和执行多中心，双盲安慰剂对照试验。符合条件的受试者有家族性或散发性ALS，根据埃尔埃斯科里亚标准诊断为临床可能，实验室支持的可能，可能或明确的ALS，并服用稳定剂量的利鲁唑至少30天。受试者通过集中式计算机平均随机分配接受锂（血清水平维持在0.4-0.8 mEq/L之间）或安慰剂。在整个研究期间，受试者、护理人员和研究者对治疗分配保持盲态。该研究使用了“事件发生时间”设计，这在ALS试验中是新颖的。事件定义为ALS功能评定量表-修订版（ALSFRS-R）评分下降≥ 6分或死亡。主要疗效分析使用对数秩检验比较锂剂组和安慰剂组之间至事件发生的时间分布。第一次中期分析发生在250名参与者中的84名被随机分组后。首次中期分析时无效的停止边界为p值≥ 0.68。由于符合无效标准，在首次意向治疗中期分析时提前终止研究。检验锂优效性的对数秩统计分析支持安慰剂（p值= 0.78）。在最终数据集中，锂剂组有22/40例受试者发生了事件，而安慰剂组有20/44例受试者发生了事件（p= 0.51）。达到主要终点的风险比的点估计值（95% CI）为1.126（0.6116 - 2.073）。没有重大安全问题。跌倒（p=0.04）和背痛（p=0.05）在锂组中明显更常见。基于观察到的效应点估计值周围的标准误，锂联合利鲁唑未达到ALS疾病进展减缓43%或更高的预定阈值，这与初步研究相矛盾。“事件发生时间”设计提高了入组率，并迅速回答了重要的临床问题，同时优化了患者资源和资金。
We studied the safety and efficacy of lithium in combination with riluzole in ALS. Recently, a pilot study demonstrated a dramatic effect of lithium in slowing ALS progression. To confirm or refute these findings, United States and Canadian funding organizations and investigators collaborated to design and execute a multicenter, double-blind placebo controlled trial in a rapid and efficient manner. Eligible participants had familial or sporadic ALS diagnosed as clinically possible, laboratory supported probable, probable, or definite ALS according to El Escorial criteria and were taking a stable dose of riluzole for at least 30 days. Subjects were equally randomized by a centralized computer to receive either lithium (serum levels maintained between 0.4-0.8 mEq/L) or placebo. Subjects, caregivers and investigators were blinded to treatment assignment throughout the study. The study used a ‘time to an event’ design, novel to ALS trials. An event was defined as ≥ 6 points drop in the ALS Functional Rating Scale-Revised (ALSFRS-R) score or death. The primary efficacy analysis used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. The first interim analysis occurred after 84 of 250 participants were randomized. The stopping boundary for futility at first interim analysis was a p-value ≥ 0.68. The study was terminated early at the first intent-to-treat interim analysis as criterion for futility was met. A log-rank statistical analysis testing the superiority of lithium favored placebo (p-value = 0.78). In the final dataset, 22/40 subjects experienced an event in the lithium group compared to 20/44 subjects in the placebo group (p= 0.51). The point estimate (95% CI) for the hazard ratio of reaching the primary endpoint was 1.126 (0.6116 to 2.073). There were no major safety concerns. Fall (p=0.04) and back pain (p=0.05) were significantly more common in the lithium group. Based on the standard error around the observed point estimate of effect, lithium in combination with riluzole did not reach the pre-specified threshold of a 43% or greater slowing in ALS disease progression which contradicts the pilot study. The ‘time to an event’ design enhanced enrollment and expeditiously answered an important clinical question while optimizing patient resources and funds.