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

doi:10.1001/jamaneurol.2022.0901

Clinical Trial

. 2022 Jun 1;79(6):575-583.

doi: 10.1001/jamaneurol.2022.0901.

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

Ryosuke Oki¹, Yuishin Izumi¹, Koji Fujita¹, Ryosuke Miyamoto¹, Hiroyuki Nodera¹, Yasutaka Sato², Satoshi Sakaguchi², Hiroshi Nokihara², Kazuaki Kanai^{3

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 Noma^{32

33}, Hiroaki Yanagawa², Satoshi Kuwabara⁸, Ryuji Kaji^{1

34}; Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators

Collaborators, Affiliations

Collaborators

Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators:
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

Affiliations

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.

PMID: 35532908
PMCID: PMC9086935
DOI: 10.1001/jamaneurol.2022.0901

Clinical Trial

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

Ryosuke Oki et al. JAMA Neurol. 2022.

. 2022 Jun 1;79(6):575-583.

doi: 10.1001/jamaneurol.2022.0901.

Authors

Collaborators

Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators:
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

Affiliations

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.

PMID: 35532908
PMCID: PMC9086935
DOI: 10.1001/jamaneurol.2022.0901

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Oki reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Izumi reported receiving grants from Japan Agency for Medical Research and Development, the Ministry of Health, Labor, and Welfare, Takeda Pharmaceutical Company Limited, and Sumitomo Dainippon Pharma Company Limited outside the submitted work. Dr Fujita reported receiving grants from the Japan Agency for Medical Research and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Miyamoto reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Nodera reported receiving grants from the Japan Agency for Medical Research and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Sato reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study. Dr Sakaguchi reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study. Dr Nokihara reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd, personal fees from Eisai Co Ltd, and honoraria for lectures outside the submitted work. Dr Kanai reported receiving grants from the Japan Agency for Medical Research and nonfinancial support from Eisai Co Ltd during the conduct of the study and grants from Grants-in-Aid for Scientific Research outside the submitted work. Dr Tsunemi reported receiving grants from the Japan Agency for Medical Research and nonfinancial support from Eisai Co Ltd and the Ministry of Health, Labor, and Welfare outside the submitted work. Dr Hattori reported receiving grants from the Japan Agency for Medical Research and nonfinancial support from Eisai Co Ltd and the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, and the Japan Science and Technology Agency, Health, and Labor; and personal fees from Sumitomo Dainippon, Takeda, Kyowa Kirin, Teijin, Novartis, Ono, Biogen, Kissei, Mitsubishi Tanabe, Hisamitsu, PARKINSON Laboratories, AbbVie, Nippon Boehringer Ingelheim, Otsuka, Bristol Myers Squibb, FP, Kissei, Nihon Medi-Physics, Daiichi-Sankyo, and Riken outside the submitted work. Dr Atsuta reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd and the Ministry of Health, Labor, and Welfare; and personal fees from Biogen, Mitsubishi Tanabe, Sumitomo Dainippon, Takeda, Novartis, and Sanofi outside the submitted work. Dr Sobue reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study; personal fees from Mitsubishi Tanabe, Sumitomo Dainippon, Nihon Pharmaceutical, Biogen, Takeda; and grants from the Japan Agency for Medical Research and Development outside the submitted work. Dr Shimizu reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Shibuya reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Ikeda reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Kano reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Nishinaka reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Kojima reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Oda reported receiving grants from the Japan Agency for Medical Research and Development and grants and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Komai reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Kikuchi reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study and nonfinancial support from Eisai Co Ltd outside the submitted work. Dr Kohara reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Urushitani reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study. Dr Nakayama reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Nagai reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Nishiyama reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Kuzume reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Shimohama reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Shimohata reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Abe reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Ishihara reported receiving grants from the Japan Agency for Medical Research and Development, Alexion Pharmaceuticals, and Mitsubishi Tanabe Pharma Development America and nonfinancial support from Eisai Co Ltd outside the submitted work. Dr Onodera reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Isose reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Araki reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Morita reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Noda reported receiving grants from the Japan Agency for Medical Research and Development and nonfinancial support from Eisai Co Ltd during the conduct of the study. Dr Maruyama reported receiving personal fees from Eisai Co Ltd, Pfizer, Takeda Pharmaceutical, Otsuka Pharmaceutical, Nihon Pharmaceutical, Teijin Pharma, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Kyowa Kirin, Novartis, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Biogen, Bristol Myers Squibb, AbbVie GK, Chugai Pharmaceutical, CSL Behring, UCB Japan, Alexion Pharmaceuticals, Amgen, Boehringer Ingelheim, Bayer, and MSD, and grants from Grants-in-Aid for Scientific Research, Eisai Co Ltd, Takeda Pharmaceutical, Otsuka Pharmaceutical, Nihon Pharmaceutical, Shionogi, Teijin Pharma, Fuji Film, Sumitomo Dainippon Pharma, Nihon Medi-Physics, Daiichi-Sankyo, Kyowa Kirin, Sanofi, Novartis, Tsumura, Japan Blood Products Organization, Pfizer, Astellas Pharma, and Mitsubishi Tanabe Pharma outside the submitted work. Dr Teramukai reported receiving personal fees from Daiichi-Sankyo, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, and Sanofi outside the submitted work. Dr Kagimura reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study. Dr Yanagawa reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study. Dr Kaji reported receiving test drug supply from Eisai Co Ltd, and grants from the Japanese Ministry of Health, Labor, and Welfare and the Japan Agency for Medical Research and Development. No other disclosures were reported.

Figures

**Figure 1.. Screening, Randomization, and Follow-up**
One patient in the placebo group was excluded from the full analysis set and safety analysis set as the patient was initially diagnosed with probable amyotrophic lateral sclerosis but was later rediagnosed with cervical spinal canal stenosis. A total of 126 patients (97%) ultimately completed the 16-week trial.

**Figure 2.. Primary Efficacy Outcomes**
The mean and slope of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score in the full analysis set are shown. Data are shown as mean (SE). Error bars indicate 95% CIs.

See this image and copyright information in PMC

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References

1. Chiò A, Logroscino G, Hardiman O, et al. ; Eurals Consortium . Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler. 2009;10(5-6):310-323. doi:10.3109/17482960802566824 - DOI - PMC - PubMed
1. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4(3):191-206. doi:10.1080/14660820310002601 - DOI - PubMed
1. Fang T, Al Khleifat A, Meurgey JH, et al. . Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018;17(5):416-422. doi:10.1016/S1474-4422(18)30054-1 - DOI - PMC - PubMed
1. Abe K, Aoki M, Tsuji S, et al. ; Writing Group; Edaravone (MCI-186) ALS 19 Study Group . Safety and efficacy of edaravone in well-defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505-512. doi:10.1016/S1474-4422(17)30115-1 - DOI - PubMed
1. Ikeda K, Iwasaki Y, Kaji R. Neuroprotective effect of ultrahigh-dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2015;354(1-2):70-74. doi:10.1016/j.jns.2015.04.052 - DOI - PubMed

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[1] Chiò A, Logroscino G, Hardiman O, et al. ; Eurals Consortium . Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler. 2009;10(5-6):310-323. doi:10.3109/17482960802566824 - DOI - PMC - PubMed

[2] Chiò A, Logroscino G, Hardiman O, et al. ; Eurals Consortium . Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler. 2009;10(5-6):310-323. doi:10.3109/17482960802566824 - DOI - PMC - PubMed

[3] Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4(3):191-206. doi:10.1080/14660820310002601 - DOI - PubMed

[4] Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4(3):191-206. doi:10.1080/14660820310002601 - DOI - PubMed

[5] Fang T, Al Khleifat A, Meurgey JH, et al. . Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018;17(5):416-422. doi:10.1016/S1474-4422(18)30054-1 - DOI - PMC - PubMed

[6] Fang T, Al Khleifat A, Meurgey JH, et al. . Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018;17(5):416-422. doi:10.1016/S1474-4422(18)30054-1 - DOI - PMC - PubMed

[7] Abe K, Aoki M, Tsuji S, et al. ; Writing Group; Edaravone (MCI-186) ALS 19 Study Group . Safety and efficacy of edaravone in well-defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505-512. doi:10.1016/S1474-4422(17)30115-1 - DOI - PubMed

[8] Abe K, Aoki M, Tsuji S, et al. ; Writing Group; Edaravone (MCI-186) ALS 19 Study Group . Safety and efficacy of edaravone in well-defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505-512. doi:10.1016/S1474-4422(17)30115-1 - DOI - PubMed

[9] Ikeda K, Iwasaki Y, Kaji R. Neuroprotective effect of ultrahigh-dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2015;354(1-2):70-74. doi:10.1016/j.jns.2015.04.052 - DOI - PubMed

[10] Ikeda K, Iwasaki Y, Kaji R. Neuroprotective effect of ultrahigh-dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2015;354(1-2):70-74. doi:10.1016/j.jns.2015.04.052 - DOI - PubMed

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

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

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