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Ultrahigh-dose methylcobalamin shows promise for early-stage ALS

By Shreeya Nanda, medwireNews Reporter

Treatment with ultrahigh-dose methylcobalamin may slow the functional decline of amyotrophic lateral sclerosis (ALS) patients with early-stage disease and a moderate progression rate, indicate Japanese trial data published in JAMA Neurology.

These findings confirm those of a post-hoc analysis of a previous phase 2/3 trial that pointed to “dose-dependent efficacy of ultrahigh-dose methylcobalamin” in this patient population, and “indicate disease-modifying, reproducible, and clinically meaningful effects” of the treatment, say Yuishin Izumi (Tokushima University Graduate School of Biomedical Sciences) and co-authors.

The double-blind, phase 3 JETALS trial started with a 12-week observation period that included 203 ambulatory patients aged 20 years or older who were diagnosed with ALS by the updated Awaji criteria within a year of symptom onset.

Of these, 130 were enrolled into the randomised 16-week treatment period – receiving either methylcobalamin 50 mg or placebo intramuscularly twice a week – having met the following criteria: a decrease of 1 or 2 points in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score; a percent forced vital capacity over 60%; and no history of noninvasive respiratory support or tracheostomy.

Among the 129 evaluable patients (median age 61 years; 57% men), the least squares mean change at 16 weeks from baseline in the primary endpoint of ALSFRS-R total score was –2.66 among methylcobalamin-treated patients and –4.63 among those given placebo. This equated to a significant absolute difference of 1.97 and a relative difference of 43% in favour of methylcobalamin.

The majority (90%) of participants were taking riluzole concomitantly, and in these patients, the absolute difference between the methylcobalamin and placebo arms with regard to the change in ALSFRS-R total score was a significant 2.11, while the relative difference was 45%.

In the overall evaluable population, methylcobalamin treatment also resulted in a significant improvement in the secondary endpoint of change in plasma homocysteine concentration, with a least squares mean difference from baseline of –1.71 versus 0.00 with placebo.

However, the least squares mean change in other secondary endpoints, such as the Norris scale total score, manual muscle test total score, and left and right grip strength, “did not show significant differences between the methylcobalamin and placebo groups”, report Izumi and colleagues.

They also aimed to assess the difference between study arms with regard to predefined events – namely, 24-hour use of noninvasive respiratory support, use of invasive respiratory support and death – but there were no events in either group during the 16-week treatment period, probably “because the patients were in the early stages of ALS and without rapid progression”.

The team continues: “Our results also confirmed that ultrahigh-dose methylcobalamin was safe during the 16-week treatment.”

Adverse events (AEs) were experienced by 62% of patients given methylcobalamin and 66% of those given placebo, with contusions (8 vs 11%), falls (6 vs 3%) and nasopharyngitis (6 vs 11%) the most common events in the methylcobalamin group.

There was one serious AE in the methylcobalamin group and two in the placebo group, but none were considered related to the study agents, and no patient in either group discontinued treatment due to AEs.

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Neurol 2022; doi:10.1001/jamaneurol.2022.0901