An ultrahigh dose of methylcobalamin safely and effectively slowed the progression of functional decline in patients with early-stage amyotrophic lateral sclerosis (ALS) with a moderate progression rate, according to study findings published in JAMA Neurology.

Riluzole and edaravone are 2 drugs approved by the US Food and Drug Administration (FDA) that aim to delay the progression of ALS. However, the effectiveness of these drugs for ALS is restricted, highlighting the need for new treatments, the researchers explained. Previous animal and human studies suggest an ultrahigh dose methylcobalamin, a form of vitamin B12, injection is safe, tolerable, and effective in slowing down functional decline in the early stages of ALS.

The objective of the current study was to assess whether intramuscular injection of methylcobalamin 50 mg twice a week effectively delayed the clinical progression of ALS in its early stages.


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Researchers conducted a multicenter, randomized, placebo-controlled, double-blind phase 3 clinical trial in Japan from October 17, 2017 to September 30, 2019. They enrolled 130 patients with ALS, dividing the patients equally into the treatment group receiving an ultrahigh dose (50 mg) of methylcobalamin and the placebo group. Of the 130 patients, 126 completed the trial with 124 continuing to the open-label extended trial period.

They assessed treatment efficacy in delaying functional decline, using the change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as a primary endpoint. Secondary endpoints assessed the patient’s ability to maintain a forced vital capacity over 60%, ambulate, and breathe independently without the need for noninvasive or invasive ventilatory support.

After 16 weeks, average ALSFRS-R scores decreased by 1.97 points more in the methylcobalamin group compared with the placebo group (-2.66 vs -4.63; 95% CI, 0.44-3.50; P =.01). In 116 patients, the combined treatment of methylcobalamin and riluzole improved their average ALSFRS-R scores by 2.11 points (95% CI, 0.46-3.76; P =.01).

Adverse effects occurred in 62% of patients in the methylcobalamin group and 66% of patients in the placebo group. Common adverse events in the methylcobalamin group included nasopharyngitis (11%), contusion (11%), constipation (6%), back pain (6%), insomnia (6%), and fall (3%). No adverse events caused treatment discontinuation and the 3 serious adverse events that occurred were not related to the investigational drug.

Study limitations included the lack of generalizability to patients in later stages of ALS, risk of including ALS mimics, shorter treatment duration of 16 weeks vs the typical 24 weeks in other clinical trials, small sample size, and lack of evaluation of specific disease-related biomarkers. Due to inclusion of patients only with early-stage ALS, noninvasive or invasive ventilatory support and patient mortality did not occur during the 16-week trial period, rendering secondary endpoints ineffective.

Overall, compared with 25 mg of methylcobalamin, a 50 mg twice weekly intramuscular injection is more likely to delay functional decline in patients with early-stage ALS with moderate progression rate.

“It is suggested that methylcobalamin at a higher concentration paradoxically upregulated gene transcription and thereby protein synthesis in vitro,” the researchers concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Oki R, Izumi Y, Fujita K, et al. Efficacy and safety of ultrahigh-dose methylcobalamin in early-stage amyotrophic lateral sclerosis: A randomized clinical trial. JAMA Neurol. Published online May 9, 2022. doi:10.1001/jamaneurol.2022.0901



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