Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.
依达拉奉在明确定义的肌萎缩侧索硬化患者中的安全性和有效性: 一项随机、双盲、安慰剂对照试验。

摘要

BACKGROUND: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.
METHODS: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.
FINDINGS: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.
INTERPRETATION: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.
FUNDING:Mitsubishi Tanabe Pharma Corporation.

译文

背景: 在之前对肌萎缩侧索硬化 (ALS) 患者的第三阶段研究中,依达拉奉在修订的 ALS 功能评定量表 (ALSFRS-R) 中没有显示出显著差异分数与安慰剂相比。对这些数据的事后分析显示,患者在 ALS 的明确或可能诊断的早期阶段,由修订的 El Escorial 标准定义, 符合一组选定的纳入标准的人显示出比整个研究人群更大的影响。我们旨在证实这一事后结果,并在一项针对符合事后分析纳入标准的早期 ALS 患者的第三阶段试验中评估依达拉奉的安全性和有效性。
方法: 在第三阶段,随机、双盲、平行组研究中,在日本 ALS 严重程度分类中,患有 1 级或 2 级 ALS 的 20-75 岁患者, 所有 12 项 ALSFRS-R 的分数至少为 2 分,强制肺活量为 80% 或更多,根据修订的 El Escorial 标准确定或可能的 ALS,从日本 31 家医院招募了 2 年或更短的疾病持续时间。在随机分组前的 12 周观察期内,符合条件的患者 ALSFRS-R 评分也下降了 1-4 分。然后,符合所有标准的患者被随机分配 1:1 接受 60 mg 静脉依达拉奉或静脉注射生理盐水安慰剂 6 个周期 (每个周期 4 周,2 周,2 周休息) 总治疗时间为 24 周。在第一周期中,研究药物或安慰剂在 14 天内每天服用一次,持续 14 天,随后是无药物期。在第二周期及其后,研究药物或安慰剂在 14 天内给药 10 天,随后是 2 周的无药物期。参与者和研究者,包括那些评估结果的人,被掩盖在治疗分配上。主要疗效结果是随机分组后 ALSFRS-R 评分从基线到 24 周 (如果是在第三个周期之后,则在停药时) 的变化。对所有接受了至少一次治疗输注、基线后至少一次评估并达到第三周期结束的患者进行了主要结果评估。对于在周期 6 末有缺失值的患者,数据由最后的观察延续 (LOCF) 方法估算,假设患者至少完成了第三个周期。对所有接受了至少一次治疗输注且在基线后至少有一次评估的患者进行安全性评估。该试验在 ClinicalTrials.gov 注册,nct01492686。
研究结果: 在 2011年11月28日至 2014 期间,我们筛选了 213 名患者,并招募了 192 名潜在参与者。其中,137 名患者完成了观察期: 69 名患者被随机分配接受依达拉奉,68 名患者被随机分配接受安慰剂。68 名服用依达拉奉的患者和 66 名服用安慰剂的患者被纳入主要疗效分析。对于主要结果,依达拉奉组的 ALSFRS-R 评分变化为-5 · 01 (SE 0 · 64) 和-7 · 50 (0 · 66) 在安慰剂组。组间的最小二乘平均差为 2 · 49 (SE 0 · 76,95% CI 0 · 99-3 · 98; p = 0 · 0013) 有利于依达拉奉。58 名 (84%) 接受依达拉奉治疗的患者和 57 名 (84%) 接受安慰剂治疗的患者报告了紧急不良事件。11 名 (16%) 服用依达拉奉的患者和 16 名 (24%) 服用安慰剂的患者有严重的不良反应,一名 (1%) 服用依达拉奉的患者和四名 (6%) 接受安慰剂的患者有不良事件 (依达拉奉组有一例吞咽困难,安慰剂组有一例呼吸困难,两例呼吸障碍,一例皮疹)这导致了撤退。
解释: 依达拉奉在一小部分肌萎缩侧索硬化症患者中显示出疗效,这些患者符合在之前第三阶段研究的事后分析中确定的标准, 与安慰剂相比,ALSFRS-R 评分下降明显较小。没有迹象表明依达拉奉可能对更多不符合标准的 ALS 患者有效。
资金来源: 三菱田边制药公司。

Edaravone

重症 依达拉奉 药物
概述  :  

依达拉奉是一种新型的自由基清除剂,于2001年4月在日本首次上市,临床主要用于治疗缺血性脑卒中。依达拉奉对神经细胞保护的作用机制主要有清除氧自由基抑制脂质过氧化反应,调控炎症因子,抑制细胞凋亡等。随着对依达拉奉的深入研究,发现除了治疗急性脑缺血外,依达拉奉对神经系统其他有氧化应激参与的疾病均有治疗作用。此外,依达拉奉还对神经系统以外的其他器官具有保护作用。   作用机制 1.依达拉奉对神经损伤的保护作用 1.1对缺血

Edaravone

释义   依达拉奉

例句   Conclusion: Edaravone can accelerate the recovery of neural function after acute cerebral infarction.结论:依达拉奉可促进急性脑梗死患者的神经功能康复。

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