Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan.
JAMA Neurol. 2022 Jun 1;79(6):575-583. doi: 10.1001/jamaneurol.2022.0901.
The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent.
To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset.
DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo.
Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks.
The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.
A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups.
Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period.
ClinicalTrials.gov Identifier: NCT03548311.
目前批准用于肌萎缩侧索硬化症（ALS）的药物疗效有限；需要开发进一步的治疗方法。初步研究表明超高剂量甲钴胺是一种很有前途的药物。
验证超高剂量甲钴胺对发病 1 年内入组的 ALS 患者的疗效和安全性。
设计、地点和参与者：这是一项多中心、安慰剂对照、双盲、随机 3 期临床试验，观察期为 12 周，随机期为 16 周，于 2017 年 10 月 17 日至 2019 年 9 月 30 日进行。患者从日本 25 个神经病学中心招募；最初入组的是根据更新的 Awaji 标准在发病 1 年内诊断为 ALS 的患者。在观察 12 周后，符合以下标准的患者有资格进行随机分组：修订版肌萎缩侧索硬化功能评定量表（ALSFRS-R）总分下降 1-2 分、用力肺活量百分比大于 60%、无无创性呼吸支持和气管切开术史、且可步行。甲钴铵组和安慰剂组的目标参与者人数均为 64 人。患者通过电子网络应答系统随机分配至甲钴铵或安慰剂组。
每周两次肌内注射甲钴铵（50mg 剂量）或安慰剂，共 16 周。
主要终点是全分析集基线至 16 周时 ALSFRS-R 总分的变化。
共有 130 名患者（平均[SD]年龄，61.0[11.7]岁；74 名男性[56.9%]）被随机分配至甲钴铵或安慰剂组（每组 65 名）。共有 129 名患者符合全分析集的纳入标准，126 名患者完成了双盲阶段。其中，124 名患者进入了开放标签扩展期。随机期的 ALSFRS-R 总分的最小二乘均数差值，甲钴铵组比安慰剂组高 1.97 分（-2.66 分比-4.63 分；95%CI，0.44-3.50；P=.01）。两组的不良反应发生率相似。
这项随机临床试验的结果表明，超高剂量甲钴胺可有效减缓早期 ALS 患者的功能下降，且进展速度中等，在 16 周的治疗期间使用是安全的。
ClinicalTrials.gov 标识符：NCT03548311。
