Ultra-high dose methylcobalamin (E0302) prolongs survival of ALS: Report of 7 years’ randomised double-blind, phase 3 clinical trial (ClinicalTrials.gov NCT00444613) (P7.060)

Abstract

OBJECTIVE: To investigate the efficacy and safety of ultra-high dose (25mg or 50mg i.m. twice weekly) of methylcobalamin compared with placebo for amyotrophic lateral sclerosis (ALS) patients. BACKGROUD: High-dose methylcobalamin showed neuroprotective effects in acrylamide neuropathy (Watanabe et al.1994) and the increase in compound muscle action potential in a trial for ALS (Kaji et al.1998). DESIGN/METHODS: Patients (373) who were diagnosed with definite, probable, or probable-laboratory-supported ALS by revised El Escorial criteria were enrolled in this study. Those with [percnt]FVC less than 60[percnt] and the disease duration more than 3 years were excluded. Patients were randomly assigned to receive placebo, 25mg, or 50mg methylcobalamin i.m. twice weekly for 182weeks. Primary endpoints were event-free survival (time until death, TIPPV or all-day NIPPV) and ALS Functional Rating Scale-Revised (ALSFRS-R) changes. RESULTS: Of 373 patients, 370 (placebo 123, 25mg 124, 50mg 123) constituted the full analysis set. In both endpoints, there was no statistical significance in the comparison for the two dose response contrasts (linear and saturate hypothesis). For the patients who were given diagnosis of ALS within 12months after the onset (placebo 48, 25mg 54, 50mg 42), the event-free survival was prolonged in a dose-dependent manner (P=0.010, hazard ratio [95[percnt]CI] vs 25mg, 50mg were 0.640 [0.377, 1.085], 0.498 [0.267, 0.929], respectively) and ALSFRS-R changes were smaller in active groups (P=0.003) than in placebo. No adverse events of particular concern were noted. DISCUSSION: The diagnosis of ALS with revised El Escorial criteria is often delayed but newly-devised Awaji criteria have enabled earlier diagnosis. Patients are less likely to benefit from ultra-high dose methylcobalamin treatment if more than 2 to 3 years have passed since the onset of ALS. CONCLUSION: The present study demonstrated for the first time that ultra-high dose methylcobalamin can significantly prolong survival and retard progression in ALS if administered early.

Disclosure: Dr. Kaji has received research support from GlaxoSmithKline and Eisai Inc. Dr. Kuzuhara has nothing to disclose. Dr. Iwasaki has nothing to disclose. Dr. Okamoto has nothing to disclose. Dr. Nakagawa has nothing to disclose. Dr. Imai has nothing to disclose. Dr. Takase has nothing to disclose. Dr. Shimizu has nothing to disclose. Dr. Tashiro has nothing to disclose.