Rare Disease Report

Early Use of Ulta-High Dose Methylcobalamin Prolongs Survival in ALS

APRIL 24, 2015
Christina T. Loguidice

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is estimated to affect approximately 2 per 100,000 persons in the US general population.1 The disease has a dire prognosis, with most patients surviving only 2 to 5 years after the diagnosis is made.1 Currently, no treatments are available that reverse the course of the disease, so the focus is on slowing the progression of symptoms, preventing complications, and taking measures to improve quality of life. During a poster session at the 67th Annual Meeting of the American Academy of Neurology, researchers from Japan presented the results of a promising randomized, double-blinded, phase 3 clinical trial (NCT00444613) that showed that early administration of ultra-high dose methylcobalamin could increase survival by a median of 600 days compared with placebo; however, early diagnosis was key to reaping these benefits.2

“ALS has been a disease of a ‘bad news’ for the patient, and as a consequence, physicians tend to delay the definitive diagnosis,” said the study’s lead researcher Ryuji Kaji, MD, PhD, professor and chairman, Department of Neurology, Institute of Health-Bioscience, Tokushima University, Tokushima, Japan, in an interview with Rare Disease Report. “Because any treatment for ALS could be too late for modifying the disease course when the disease has elapsed too long, strategies for earlier diagnosis are essential,” he added.
The study used the revised El Escorial criteria to identify patients for enrollment. Patients were included in the study if they had a diagnosis of definite, probable, or probable–laboratory-supported ALS using these criteria; had a forced vital capacity of more than 60%; and had a disease duration of less than 3 years. This yielded 373 patients, with 370 patients constituting the full analysis set. Of the 370 study participants, 123 were randomly assigned to placebo, 124 to methylcobalamin 25 mg, and 123 to methylcobalamin 50 mg.
The study’s primary endpoints included event-free survival (time until death, tracheostomy intermittent positive pressure ventilation, or all-day nasal intermittent positive pressure ventilation) and changes on the ALS Functional Rating Scale-Revised (ALSFRS-R). The researchers found no statistical significance in the comparison for the 2 dose-response contrasts (linear and saturate hypothesis). However, patients who received an ALS diagnosis within 12 months after the onset of symptoms had a prolonged event-free survival that was dose-dependent, with a hazard ratio [HR] of 0.640 (range, 0.377-1.085) in the 50-mg group compared with an HR of 0.498 (range, 0.267-0.929) in the 25-mg group (P = .010).
Also, fewer ALSFRS-R changes were observed in both treatment groups compared with placebo (P = .003). Methylcobalamin was well tolerated, with no major adverse events reported.

“Because ultra-high dose intramuscular methylcobalamin (50 mg) significantly prolonged survival in patients who were treated early after their ALS diagnosis, and future treatments may demonstrate similar findings, we need tools that can facilitate earlier diagnosis of ALS,” said Dr. Kaji. “Since our study was initiated 7 years ago, the Awaji-Shima criteria have become available. We believe these criteria will improve diagnosis, but this is an area that warrants further investigation.”


1. Facts you should know. ALS Association website. http://www.alsa.org/about-als/facts-you-should-know.html. Accessed April 23, 2015.
2. Kaji R, Kuzuhara S, Iwasaki Y, et al. Ultra-high dose methylcobalamin (E0302) prolongs survival of ALS: randomized double-blind, phase 3 clinical trial (ClinicalTrials.gov NCT00444613). Poster presented at: 67th Annual Meeting of the American Academy of Neurology; April 18-25, 2015; Washington, DC.

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