Ryosuke Oki1, Yuishin Izumi1, Koji Fujita1, Ryosuke Miyamoto1, Hiroyuki Nodera1, Yasutaka Sato2, Satoshi Sakaguchi2, Hiroshi Nokihara2, Kazuaki Kanai3,4, Taiji Tsunemi4, Nobutaka Hattori4, Yuki Hatanaka5, Masahiro Sonoo5, Naoki Atsuta6, Gen Sobue6, Toshio Shimizu7, Kazumoto Shibuya8, Ken Ikeda9, Osamu Kano9, Kazuto Nishinaka10, Yasuhiro Kojima11, Masaya Oda12, Kiyonobu Komai13, Hitoshi Kikuchi14, Nobuo Kohara15, Makoto Urushitani16, Yoshiaki Nakayama17, Hidefumi Ito17, Makiko Nagai18, Kazutoshi Nishiyama18, Daisuke Kuzume19, Shun Shimohama20, Takayoshi Shimohata21, Koji Abe22, Tomohiko Ishihara23, Osamu Onodera23, Sagiri Isose24, Nobuyuki Araki24, Mitsuya Morita25, Kazuyuki Noda26, Tatsushi Toda27, Hirofumi Maruyama28, Hirokazu Furuya29, Satoshi Teramukai30, Tatsuo Kagimura31, Kensuke Noma32,33, Hiroaki Yanagawa2, Satoshi Kuwabara8, Ryuji Kaji1,34. 1. Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. 2. Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan. 3. Department of Neurology, Fukushima Medical University School of Medicine, Fukushima, Japan. 4. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. 5. Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan. 6. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 7. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan. 8. Department of Neurology, Chiba University Graduate School of Medicine, Chiba, Japan. 9. Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan. 10. Department of Neurology, Sumitomo Hospital, Osaka, Japan. 11. Department of Neurology, Takeda General Hospital, Kyoto, Japan. 12. Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Japan. 13. Department of Neurology, National Hospital Organization Iou Hospital, Kanazawa, Japan. 14. Department of Neurology, Murakami Karindoh Hospital, Fukuoka, Japan. 15. Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan. 16. Department of Neurology, Shiga University of Medical Science, Otsu, Japan. 17. Department of Neurology, Wakayama Medical University, Wakayama, Japan. 18. Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan. 19. Department of Neurology, Chikamori Hospital, Kochi, Japan. 20. Department of Neurology, Sapporo Medical University, Sapporo, Japan. 21. Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan. 22. Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. 23. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. 24. Department of Neurology, National Hospital Organization Chibahigashi Hospital, Chiba, Japan. 25. Division of Neurology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan. 26. Department of Neurology, Juntendo University Shizuoka Hospital, Izunokuni, Japan. 27. Department of Neurology, The University of Tokyo, Tokyo, Japan. 28. Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. 29. Department of Neurology, Kochi Medical School, Kochi University, Nankoku, Japan. 30. Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. 31. Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation, Kobe, Japan. 32. Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan. 33. Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 34. Department of Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan.
Abstract
Importance: 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. Objective: 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. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.
Importance: 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. Objective: 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. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.
Authors: Nimeshan Geevasinga; Clement T Loy; Parvathi Menon; Mamede de Carvalho; Michael Swash; Maarten Schrooten; Philip Van Damme; Malgorzata Gawel; Masahiro Sonoo; Mana Higashihara; Yu-Ichi Noto; Satoshi Kuwabara; Matthew C Kiernan; Petra Macaskill; Steve Vucic Journal: Clin Neurophysiol Date: 2016-04-16 Impact factor: 3.708
Authors: Stephanie R Shepheard; Joanne Wuu; Michell Cardoso; Luke Wiklendt; Phil G Dinning; Tim Chataway; David Schultz; Michael Benatar; Mary-Louise Rogers Journal: Neurology Date: 2017-02-22 Impact factor: 9.910
Authors: Rita Mejzini; Loren L Flynn; Ianthe L Pitout; Sue Fletcher; Steve D Wilton; P Anthony Akkari Journal: Front Neurosci Date: 2019-12-06 Impact factor: 4.677
Authors: Stephen A Johnson; Ton Fang; Fabiola De Marchi; Dylan Neel; Donatienne Van Weehaeghe; James D Berry; Sabrina Paganoni Journal: Drugs Date: 2022-09-19 Impact factor: 11.431