Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

医学 安慰剂 依达拉奉 肌萎缩侧索硬化 内科学 物理医学与康复 多发性硬化 双盲 麻醉 疾病 精神科 病理 替代医学
作者
Koji Abe,Masashi Aoki,Shoji Tsuji,Yasuto Itoyama,Gen Sobue,Masanori Togo,Chikuma Hamada,Masahiko Tanaka,Makoto Akimoto,Kazue Nakamura,Fumihiro Takahashi,Kazuoki Kondo,Hiide Yoshino,Koji Abe,Masashi Aoki,Shoji Tsuji,Yasuto Itoyama,Gen Sobue,Masanori Togo,Chikuma Hamada
出处
期刊:Lancet Neurology [Elsevier BV]
卷期号:16 (7): 505-512 被引量:813
标识
DOI:10.1016/s1474-4422(17)30115-1
摘要

Summary

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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
hzh完成签到 ,获得积分10
1秒前
gg发布了新的文献求助10
1秒前
勤劳滑板完成签到 ,获得积分10
1秒前
Jerry完成签到,获得积分10
2秒前
MrLiu完成签到,获得积分10
3秒前
冷傲博完成签到,获得积分10
3秒前
jeff完成签到,获得积分10
3秒前
LHZ完成签到,获得积分10
3秒前
所所应助时尚俊驰采纳,获得10
4秒前
影子芳香完成签到 ,获得积分10
5秒前
6秒前
6秒前
不必要再讨论适合与否完成签到,获得积分0
7秒前
无情夏寒完成签到 ,获得积分10
8秒前
慕青应助马士全采纳,获得10
9秒前
xuzj应助科研通管家采纳,获得10
9秒前
Rubby应助科研通管家采纳,获得30
10秒前
SciGPT应助科研通管家采纳,获得10
10秒前
10秒前
10秒前
shiizii应助科研通管家采纳,获得10
10秒前
10秒前
10秒前
10秒前
ludong_0应助科研通管家采纳,获得10
10秒前
YeeYee发布了新的文献求助10
10秒前
冷酷的松思完成签到,获得积分10
10秒前
zgt01发布了新的文献求助10
11秒前
zhang完成签到,获得积分10
11秒前
江中完成签到 ,获得积分10
13秒前
13秒前
阿玖完成签到 ,获得积分10
14秒前
jiaolulu发布了新的文献求助10
16秒前
踏雪飞鸿完成签到,获得积分10
17秒前
hannah完成签到,获得积分10
17秒前
songvv发布了新的文献求助10
18秒前
一一一应助Bin_Liu采纳,获得10
19秒前
麻果完成签到,获得积分10
21秒前
OER完成签到,获得积分10
21秒前
伦语完成签到,获得积分20
21秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038201
求助须知:如何正确求助?哪些是违规求助? 3575940
关于积分的说明 11373987
捐赠科研通 3305747
什么是DOI,文献DOI怎么找? 1819274
邀请新用户注册赠送积分活动 892662
科研通“疑难数据库(出版商)”最低求助积分说明 815022