発症早期ALS患者に対する超高用量メチルコバラミンの有効性・安全性について : ランダム化比較試験
沖, 良祐 徳島大学大学院医学研究科（医学専攻）
Sato, Yasutaka Tokushima University
軒原, 浩 Tokushima University
Kanai, Kazuaki Fukushima Medical University|Juntendo University
Tsunemi, Taiji Juntendo University
Hattori, Nobutaka Juntendo University
Hatanaka, Yuki Teikyo University
Sonoo, Masahiro Teikyo University
Atsuta, Naoki Nagoya University
Sobue, Gen Nagoya University
Shimizu, Toshio Tokyo Metropolitan Neurological Hospital
Shibuya, Kazumoto Chiba University
Ikeda, Ken Toho University
Kano, Osamu Toho University
Nishinaka, Kazuto Sumitomo Hospital
Kojima, Yasuhiro Takeda General Hospital
Oda, Masaya Vihara Hananosato Hospital
Komai, Kiyonobu National Hospital Organization lou Hospital
Kikuchi, Hitoshi Murakami Karindoh Hospital
Kohara, Nobuo Kobe City Medical Center General Hospital
Urushitani, Makoto Shiga University of Medical Science
Nakayama, Yoshiaki Wakayama Medical University
Ito, Hidefumi Wakayama Medical University
Nagai, Makiko Kitasato University
Nishiyama, Kazutoshi Kitasato University
Kuzume, Daisuke Chikamori Hospital
Shimohama, Shun Sapporo Medical University
Shimohata, Takayoshi Gifu University
Abe, Koji Okayama University
Ishihara, Tomohiko Niigata University
Onodera, Osamu Niigata University
Isose, Sagiri National Hospital Organization Chibahigashi Hospital
Araki, Nobuyuki National Hospital Organization Chibahigashi Hospital
Morita, Mitsuya Jichi Medical University
Noda, Kazuyuki Juntendo University
Toda, Tatsushi The University of Tokyo
Maruyama, Hirofumi Hiroshima University
Furuya, Hirokazu Kochi University
Teramukai, Satoshi Kyoto Prefectural University of Medicine
Kagimura, Tatsuo Foundation for Biomedical Research and Innovation
Noma, Kensuke Hiroshima University
Kuwabara, Satoshi Chiba University
Amyotrophic Lateral Sclerosis (ALS)
Updated Awaji criteria
Post hoc analysis in a phase 2/3 trial indicated ultra-high dose methylcobalamin slowed decline of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 16 as well as at week 182, without increase of adverse events, in patients with amyotrophic lateral sclerosis (ALS) who were enrolled within 1 year from onset.
To validate the efficacy and safety of ultra-high dose methylcobalamin for patients with ALS enrolled within 1 year of onset.
A multicenter, placebo-controlled, double-blind, randomized phase 3 trial with 12-week observation and 16-week randomized period, conducted from October 2017 to September 2019.
Twenty-five neurology centers in Japan.
Patients 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 ALSFRS-R total score, a percent forced vital capacity over 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulant. The target number was 64 in both methylcobalamin and placebo groups. Of 203 patients enrolled in the observation, 130 patients (age, 61.0 ± 11.7 years; female, 56) met the criteria and were randomly assigned through an electronic web-response system to methylcobalamin or placebo (65 for each). Of these, 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage.
Intramuscular injection of methylcobalamin 50 mg or placebo twice weekly for 16 weeks.
Main outcomes and measures:
The primary endpoint was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.
The least-squares mean difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 versus −4.63; 95% CI, 0.44–3.50; P = 0.012). The incidence of adverse events was similar between the two groups.
Conclusions and relevance:
Ultra-high dose methylcobalamin was efficacious in slowing functional decline and safe in the 16-week treatment period in ALS patients in the early stage and with moderate progression rate.
UMIN-CTR Identifier: UMIN000029588 (umin.ac.jp/ctr); ClinicalTrials.gov Identifier: NCT03548311 (clinicaltrials.gov)
American Medical Association
k3738_abstract.pdf 151 KB
k3738_review.pdf 216 KB
k3738_fulltext.pdf 497 KB
Supplementary File.pdf 882 KB