Lancet Neurol. 2017 Jul;16(7):505-512. doi: 10.1016/S1474-4422(17)30115-1. Epub 2017 May 15.
In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria.
In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686.
Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5·01 (SE 0·64) in the edavarone group and -7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal.
Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.
Mitsubishi Tanabe Pharma Corporation.
在先前一项针对肌萎缩侧索硬化症（ALS）患者的 3 期研究中，依达拉奉与安慰剂相比，在修订后的 ALS 功能评定量表（ALSFRS-R）评分方面并未显示出显著差异。对这些数据的事后分析显示，符合修订后的埃尔埃斯科里亚尔标准的、明确或可能诊断为 ALS 的早期患者，满足一组特定的纳入标准，其效果比整个研究人群更为显著。我们旨在证实这一事后分析结果，并在一项专注于符合事后分析纳入标准的早期 ALS 患者的 3 期试验中评估依达拉奉的安全性和疗效。
在这项 3 期、随机、双盲、平行组研究中，从日本 31 家医院招募了年龄在 20-75 岁之间、日本 ALS 严重程度分类为 1 或 2 级、ALSFRS-R 所有 12 项评分至少 2 分、用力肺活量 80%或以上、根据修订后的埃尔埃斯科里亚尔标准明确或可能诊断为 ALS 且病程 2 年或以下的 ALS 患者。符合条件的患者在随机分组前的 12 周观察期内，ALSFRS-R 评分也下降了 1-4 分。所有符合标准的患者随后被随机分配 1:1 接受 60mg 静脉内依达拉奉或静脉内生理盐水安慰剂治疗 6 个周期（每个周期 4 周，2 周治疗，2 周停药），总治疗持续时间为 24 周。在第 1 周期中，在 14 天的治疗期内，每天给予研究药物或安慰剂 1 次，持续 14 天，然后进行无药物治疗期。在第 2 周期及以后，在 14 天的治疗期内，每天给予研究药物或安慰剂 10 天，然后进行 2 周的无药物治疗期。参与者和研究者，包括评估结局的人员，对治疗分配均处于盲态。主要疗效结局是从基线到随机分组后 24 周（或如果在第三个周期后停药）的 ALSFRS-R 评分变化。主要结局在所有接受至少一次治疗输注、至少有一次基线后评估且完成第 3 周期的患者中进行评估。对于第 6 周期结束时缺失值的患者，采用最后一次观测值结转（LOCF）法进行数据填补，前提是患者至少完成了第 3 周期。所有接受至少一次治疗输注且至少有一次基线后评估的患者均进行安全性评估。该试验在 ClinicalTrials.gov 注册，编号为 NCT01492686。
在 2011 年 11 月 28 日至 2014 年 9 月 3 日期间，我们筛选了 213 名患者，并纳入了 192 名作为潜在参与者。其中，137 名患者完成了观察期：69 名被随机分配接受依达拉奉，68 名被随机分配接受安慰剂。68 名接受依达拉奉治疗的患者和 66 名接受安慰剂治疗的患者被纳入主要疗效分析。对于主要结局，依达拉奉组的 ALSFRS-R 评分变化为-5.01（SE 0.64），安慰剂组为-7.50（0.66）。组间最小二乘均数差异为 2.49（SE 0.76，95%CI 0.99-3.98；p=0.0013），有利于依达拉奉。接受依达拉奉治疗的 58 名（84%）患者和接受安慰剂治疗的 57 名（84%）患者报告了治疗出现的不良事件。11 名（16%）接受依达拉奉治疗的患者和 16 名（24%）接受安慰剂治疗的患者发生了严重不良事件，1 名（1%）接受依达拉奉治疗的患者和 4 名（6%）接受安慰剂治疗的患者发生了不良事件（依达拉奉组 1 例吞咽困难，安慰剂组 1 例呼吸困难，2 例呼吸障碍，1 例皮疹），导致退出。
依达拉奉在先前一项 3 期研究的事后分析中确定的标准下，对符合条件的一小部分 ALS 患者显示出疗效，与安慰剂相比，其 ALSFRS-R 评分下降幅度明显更小。没有迹象表明依达拉奉可能对不符合标准的更广泛的 ALS 患者群体有效。
Mitsubishi Tanabe Pharma Corporation。
