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Original Investigation
May 9, 2022

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • 2Clinical Research Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan
  • 3Department of Neurology, Fukushima Medical University School of Medicine, Fukushima, Japan
  • 4Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
  • 5Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan
  • 6Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • 7Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
  • 8Department of Neurology, Chiba University Graduate School of Medicine, Chiba, Japan
  • 9Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan
  • 10Department of Neurology, Sumitomo Hospital, Osaka, Japan
  • 11Department of Neurology, Takeda General Hospital, Kyoto, Japan
  • 12Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Japan
  • 13Department of Neurology, National Hospital Organization Iou Hospital, Kanazawa, Japan
  • 14Department of Neurology, Murakami Karindoh Hospital, Fukuoka, Japan
  • 15Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan
  • 16Department of Neurology, Shiga University of Medical Science, Otsu, Japan
  • 17Department of Neurology, Wakayama Medical University, Wakayama, Japan
  • 18Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan
  • 19Department of Neurology, Chikamori Hospital, Kochi, Japan
  • 20Department of Neurology, Sapporo Medical University, Sapporo, Japan
  • 21Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan
  • 22Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
  • 23Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
  • 24Department of Neurology, National Hospital Organization Chibahigashi Hospital, Chiba, Japan
  • 25Division of Neurology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan
  • 26Department of Neurology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
  • 27Department of Neurology, The University of Tokyo, Tokyo, Japan
  • 28Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
  • 29Department of Neurology, Kochi Medical School, Kochi University, Nankoku, Japan
  • 30Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • 31Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation, Kobe, Japan
  • 32Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
  • 33Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
  • 34Department of Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan
JAMA Neurol. 2022;79(6):575-583. doi:10.1001/jamaneurol.2022.0901
Key Points

Question  Does twice-weekly intramuscular injection of 50-mg ultrahigh-dose methylcobalamin slow clinical progression in early-stage amyotrophic lateral sclerosis?

Findings  In this randomized phase 3 clinical trial that included 130 participants who were enrolled within 1 year from symptom onset and presented with a 1- or 2-point decrease on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale total score during 12 weeks of observation, the changes in the score were −2.66 with methylcobalamin vs −4.63 with placebo during the 16-week treatment, which significantly differed.

Meaning  Ultrahigh-dose methylcobalamin may slow functional decline in early-stage amyotrophic lateral sclerosis with moderate progression rate.


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

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    3 Comments for this article
    Does ultra high dose methylcobalamin confer similar benefits in other neurodegenerative diseases?
    DAVID KELLER, M.D.,M.S. | Cleveland Clinic Journal of Medicine
    Amyotrophic Lateral Sclerosis (ALS) shares certain pathophysiological similarities with other neurodegenerative diseases of the CNS, including Alzheimer's Disease (AD) and Parkinson's Disease (PD).

    Could ultra high doses of methylcobalamin cause a similar slowing of the progression of cognitive dysfunction in AD, or motor dysfunction in PD?

    Should similar randomized clinical trials of ultra high dose methylcobalamin versus placebo be conducted for patients with AD or PD?
    Alternative actions of methylcobalamin to account for therapeutic effects
    Nicola Mercuri, Professor of Neurology | Neurological Clinic, University of Tor Vergata Rome Italy
    I read with attention the manuscript demonstrating that high doses of methylcobalamin have disease-modifying effects on ALS patients.
    Regarding the action of the vitamin, I would suggest, based on our observations, that it might decrease the brain's content of hydrogen sulfur (H2S), which is highly toxic to neurons being peculiarly high in ALS (Davoli et al., Ann Neurol. 2015 Apr;77(4):697-709).
    Cobalt present in the vitamin might absorb H2S, limiting the gas-induced damage to neurons.
    Absolute protection of H2S decreasing drugs has been shown to be caused by the pharmacological inhibition of H2S production in the SOD1G93A-ALS Mouse Model
    (Spalloni et al., Int J Mol Sci. 2019 May 24;20(10):2550).
    Shortcomings of neurologic scales and minimal clinically significant differences
    Joao Paulo Telles, MD, PhD | Department of Neurology, University of Sao Paulo
    Outcome scales are always somewhat arbitrary and never fully capture an individual’s health state. Nevertheless, they are among the best and most common surrogate outcomes. The RESCUE-Japan-LIMIT(1) trial defined a modified Rankin Scale of 0-3 as the primary endpoint, which might include significantly disabled patients, not to mention the many aspects not captured in that scale, such as depression or aphasia, which might largely increase the burden of disease(2).
    If trials like the RESCUE-Japan-LIMIT provoke thoughts on whether expanded definitions of good outcomes are indeed “good”, trials like JETALS provoke thoughts on when are clinical outcomes significant. The trial reported
    a LSMD of 1.97, with a lower confidence interval boundary of 0.44, which raises two main discussion topics.
    The first point is the minimal clinically important difference (MCID). Is a 2-point difference on a 48-point scale, considering the 95%CI almost reaching 0, significant to the patient with ALS? MCIDs can be assessed using expert consensus (Delphi method), patient assessment (anchor methods), or distribution methods(3). It would be interesting to evaluate if the observed difference is above the MCID.
    The second point is the multidimensionality of the ALSFRS-R: a 2-point decrease could represent a change from “continuous BiPAP during nighttime” to “invasive mechanical ventilation,” or it could represent a change from “normal” handwriting to “not all words intelligible.” Previous analyses show that the ALSFRS-R encompasses three distinct domains in one scale (bulbar, respiratory, and fine/gross motor function)(4), which might hinder a clear-cut understanding of a patient’s status based on a single crude number. As with the RESCUE-Japan-LIMIT, using scales as outcomes in neurology trials is always a trade-off between oversimplifying an evaluation and losing unidimensionality; between clustering together different functional statuses and finding possibly marginally significant differences.
    While both aspects are interesting, one cannot forget that methylcobalamin is very inexpensive and ALS is a devastating condition lacking disease-modifying treatments other than riluzole. Therefore, even if the effects are modest and the ALSFRS-R is flawed, it is probably worth doing, from the patient, physician, and healthcare system perspectives.

    Joao Paulo Mota Telles, Eberval Gadelha Figueiredo
    Department of Neurology, University of Sao Paulo


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