Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis
Authors: Ryosuke Oki, Yuishin Izumi, Koji Fujita, Ryosuke Miyamoto, Hiroyuki Nodera, Yasutaka Sato, Satoshi Sakaguchi, Hiroshi Nokihara, Kazuaki Kanai, Taiji Tsunemi, Nobutaka Hattori, Yuki Hatanaka, Masahiro Sonoo, Naoki Atsuta, Gen Sobue, Toshio Shimizu, Kazumoto Shibuya, Ken Ikeda, Osamu Kano, Kazuto Nishinaka, Yasuhiro Kojima, Masaya Oda, Kiyonobu Komai, Hitoshi Kikuchi, Nobuo Kohara, Makoto Urushitani, Yoshiaki Nakayama, Hidefumi Ito, Makiko Nagai, Kazutoshi Nishiyama, Daisuke Kuzume, Shun Shimohama, Takayoshi Shimohata, Koji Abe, Tomohiko Ishihara, Osamu Onodera, Sagiri Isose, Nobuyuki Araki, Mitsuya Morita, Kazuyuki Noda, Tatsushi Toda, Hirofumi Maruyama, Hirokazu Furuya, Satoshi Teramukai, Tatsuo Kagimura, Kensuke Noma, Hiroaki Yanagawa, Satoshi Kuwabara, Ryuji Kaji, Yusuke Osaki, Hiroki Yamazaki, Shotaro Haji, Yumi Ishida, Akari Futami, Toshiko Miyamoto, Akiyo Akaishi, Kenshi Takechi, Kazuki Maeda, Shoko Kurisu, Mari Yoshizawa, Nozomu Matsuda, Tomoko Nakazato, Ryoichi Nakamura, Naoki Hayashi, Akihiro Kawata, Hideki Kimura, Kota Bokuda, Akiko Tamura, Chiho Ishida, Michi Kawamoto, Hyo Kim, Jun Kawamata, Shin Hisahara, Yuichi Kimura, Toru Yamashita, Yasuyuki Ohta, Kimihito Arai, Takahiro Takeda, Tomoo Ogawa, Shingo Ikari, Yasunori Ono, Yukio Fujino
Journal: JAMA Neurology (2022)

<h3>Importance</h3> 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. <h3>Objective</h3> To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. <h3>Main Outcomes and Measures</h3> The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. <h3>Results</h3> 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;<i>P</i> = .01). The incidence of adverse events was similar between the 2 groups. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03548311