This randomized phase 3 clinical trial, conducted between October 2017 and September 2019, investigated the efficacy and safety of ultrahigh-dose methylcobalamin (50 mg) in early-stage amyotrophic lateral sclerosis (ALS). A total of 130 patients who had been diagnosed within one year of symptom onset and experienced a moderate progression rate (defined as a 1-2 point decrease in the ALS Functional Rating Scale-Revised [ALSFRS-R]) were randomized to receive either the active treatment or a placebo. Over the 16-week treatment period, patients receiving methylcobalamin showed a statistically significant reduction in functional decline compared to the placebo group. The least square mean difference in ALSFRS-R total score was 1.97 points in favor of methylcobalamin (−2.66 vs −4.63; 95% CI, 0.44–3.50; P = .01), equating to a 43% slower rate of deterioration. This slowing of progression was especially notable in fine and gross motor functions, but no significant changes were observed in bulbar or respiratory functions.

In addition to ALSFRS-R outcomes, the study examined other clinical measures, including forced vital capacity (FVC), manual muscle test scores, and plasma homocysteine concentrations. While there were no significant differences between the methylcobalamin and placebo groups for FVC and muscle test scores, a marked reduction in plasma homocysteine levels was observed in the treatment group (−1.71; 95% CI, −1.14 to −2.29; P < .001). This finding aligns with methylcobalamin's proposed mechanism of action as a coenzyme involved in reducing neurotoxic homocysteine levels, which are elevated in ALS patients. Importantly, 90% of patients were also receiving riluzole, and the combined use of methylcobalamin and riluzole led to a 45% reduction in clinical decline, suggesting a potential synergistic effect between the two treatments.

Regarding safety, the incidence of adverse events was similar between the methylcobalamin and placebo groups, with 62% of patients in the methylcobalamin group and 66% in the placebo group reporting side effects. Notably, there were three serious adverse events: one case of cerebral infarction in the methylcobalamin group and two unrelated events in the placebo group (hemorrhoid surgery and tracheostoma stenosis). No adverse events led to discontinuation of treatment, and overall, ultrahigh-dose methylcobalamin was considered safe and well-tolerated during the 16-week study period. Given the efficacy in slowing disease progression and the low incidence of severe side effects, the study concluded that ultrahigh-dose methylcobalamin is a promising therapeutic option for early-stage ALS patients with moderate progression rates.