Since our review, the 373 patient trial we described seeing at a meeting has been published (J Neurol Neurosurg Psychiatry 2019;90:451-457). Again, this did not show an overall benefit for patients with ALS. In a subgroup of patients in the first 12 months of their symptoms, MeCbl was associated with slower ALSFRS-R progression and longer survival. A very recently published follow up study focused only on patients in the first 12 months of their ALS symptoms with an ALSFRS-R progression rate of 1-2 points over a 12-week lead in (JAMA Neurol 2022;May 9:epub). Again, this was randomized, double-blind and placebo controlled. This study showed that patients on 50-mg IM twice weekly had significantly slower ALSFRS-R progression over 12 weeks than those on placebo. This study was well designed. We change our Trials grade to A, but caution that both trials only show benefit from treatment in patients who are in the first year of their ALS symptoms. We see no evidence that MeCbl helps patients who have had symptoms for longer than 1 year.
Key Information
MeCbl has promising mechanisms and positive preclinical data from two different ALS models. Unfortunately, the anecdotal data we found did not identify any clear specific benefit, and the best of three clinical trials was unable to show an overall difference in ALSFRS-R progression or survival between PALS treated with MeCbl and those treated with placebo (26). A sub-group of patients with very specific pretreatment progression rates of 1–3 ALSFRS-R points over 12 weeks, and very early disease (less than 12 months from symptom onset) may have had benefit (26). This finding needs to be replicated, especially since an earlier study suggested patients with longer disease duration were more likely to benefit (20). We would like to see a full traditional sub-group analysis (28) carried out on the data from the third trial (26). This sub-group analysis could then be used to design inclusion criteria for a new phase III trial comparing MeCbl 50 mg twice a week IM to placebo. The new trial could measure serum B12 and homocysteine, and have pre-planned sub-group analyses that are both logical and practical. While we wait for this, PALS who wish to try MeCbl are reminded that the above studies used very high, injected doses, which appear to be available only by prescription. Lower over-the-counter doses administered orally have not been studied. It is well established that over-the-counter oral supplements may be of poor and inconsistent quality (32). Some over-the-counter oral vitamin B supplements contain not only B12 but also B6, which in large quantities can be harmful to the nervous system (33).