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Research paper
Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study
  1. Ryuji Kaji1,
  2. Takashi Imai2,3,
  3. Yasuo Iwasaki4,
  4. Koichi Okamoto5,
  5. Masanori Nakagawa6,
  6. Yasuo Ohashi7,
  7. Takao Takase8,
  8. Takahisa Hanada8,
  9. Hiroki Shimizu8,
  10. Kunio Tashiro9,
  11. Shigeki Kuzuhara10
  1. 1 Department of Neurology, Tokushima University Hospital, Tokushima, Japan
  2. 2 National Hospital Organization Miyagi National Hospital, Sendai, Japan
  3. 3 Tokushukai ALS Care Center, Tokushukai, Japan
  4. 4 Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan
  5. 5 Department of Neurology, Geriatrics Research Institute and Hospital, Maebashi, Gunma, Japan
  6. 6 North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan
  7. 7 Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Hachioji, Japan
  8. 8 Eisai, Tokyo, Japan
  9. 9 Department of Neurology, Hokuyukai Neurological Hospital, Sapporo, Japan
  10. 10 School of Nursing, Suzuka University of Medical Science, Suzuka, Japan
  1. Correspondence to Professor Ryuji Kaji, Department of Neurology, Tokushima University School of Medicine, Tokushima 770-8503, Japan; rkaji{at}tokushima-u.ac.jp

Abstract

Objective To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).

Methods 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset).

Results No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months’ duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups.

Conclusion Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.

Trial registration number NCT00444613.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Contributions RK designed the study, interpreted the data and drafted the manuscript. TI designed the study. YI designed the study. KO designed the study. MN designed the study. YO designed the study and performed the statistical analysis. TT designed the study, performed the statistical analysis, interpreted the data and drafted the manuscript. TH interpreted the data and drafted the manuscript. HS designed the study, interpreted the data and drafted the manuscript. KT designed the study and interpreted the data. SK designed the study and interpreted the data.

  • Funding This study was funded by Eisai.

  • Competing interests RK received grants from Eisai during the conduct of the study and has a patent on the Method of treating amyotrophic lateral sclerosis (US 20130344081 A1 licensed). TI received grants from Eisai during the conduct of the study. YI reports no disclosures. KO reports no disclosures. MN reports no disclosures. YO received personal fees from Statcom, Sanofi, Eisai, Chugai, Taiho, Shionogi and Kowa, and non-financial support from Yakult Honsha and Takeda outside the submitted work. TT is employed by Eisai. TH is employed by Eisai. HS is employed by Eisai. KT received grants from Eisai during the conduct of the study. SK received grants from Eisai during the conduct of the study.

  • Patient consent for publication Not required.

  • Ethics approval This study is conducted in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the institutional review board at each centre. All eligible patients provided written informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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