Lithium carbonate in amyotrophic lateral sclerosis Lack of efficacy in a dose-finding trial
Lithium carbonate in amyotrophic lateral sclerosis Lack of efficacy in a dose-finding trial
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DOI：
10.1212/wnl.0b013e3181ed9e7c
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发表时间：
2010-08-17
期刊：
影响因子：
9.9
通讯作者：
Beghi, E.
中科院分区：
文献类型：
--
作者：
Chio, A.;Borghero, G.;Beghi, E.
背景：最近报道了锂对肌萎缩侧索硬化症（ALS）的神经保护作用。我们进行了一项碳酸锂多中心试验，以评估其对 ALS 患者的耐受性、安全性和有效性，比较了 2 种不同的目标血液水平（0.4-0.8 mEq/L，治疗组 [TG]，与 0.2-0.4 mEq/L，亚治疗组 [STG]）。方法：该研究是一项多中心、单盲、随机、剂量探索试验，于 2008 年 5 月至 11 月进行2009 年在 21 个意大利 ALS 中心开展。该试验在意大利药品管理局的公共数据库 (http://oss-sper-clin.agenziafarmaco.it/) 注册（EudraCT 编号 2008-001094-15）。 结果：截至 2009 年 10 月，共有 171 名患者入组，其中 87 名随机分配至 TG，84 名随机分配至 STG。根据方案进行的中期数据分析显示，117 名患者 (68.4%) 由于死亡/气管切开术/严重残疾、不良事件 (AE)/严重 AE (SAE) 或缺乏疗效而终止了研究。数据监测委员会建议于 2009 年 11 月 2 日停止试验。结论：在这组 ALS 患者中，即使是亚治疗剂量，锂的耐受性也不佳。两种剂量在生存/严重残疾和功能数据方面相当。相对较高的 AE/SAE 发生率和锂的耐受性降低，引发了人们对其在 ALS 中的安全性的严重怀疑。证据分类：该研究提供了 II 类证据，表明治疗性碳酸锂 (0.4-0.8 mEq/L) 与亚治疗性碳酸锂 (0.2-0.4 mEq/L) 在 ALS 疗效的主要结局（生存/自主权丧失）方面没有差异。由于患者认为缺乏疗效和不良事件，这两个目标水平导致超过 30% 的参与者退出。神经病学(R)2010; 75：619-625
Background: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]).Methods: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15).Results: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009.Conclusions: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. Classification of evidence: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs. Neurology (R) 2010; 75: 619-625