A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial

Abstract

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were –7.0 ± 7.1 and –0.04 ± 0.1, respectively, in the riluzole group and –6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future.

Key words::

• Mexiletine
• sodium current
• amyotrophic lateral sclerosis
• clinical trial
• nerve excitability

Acknowledgements

Shibuya, Misawa and Kuwabara receive research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (KS, 90507360; SM, 30375753; SK, 70282481). Shibuya receives funding support from the Nakabayashi Trust for ALS research.

This trial is supported by the Nakabayashi Trust for ALS research. Shibuya, Misawa, Kimura, Noto, Sato, Iwai, Sekiguchi, Mitsuma, Beppu, Watanabe, Sawaguchi and Hanaoka have no disclosure. Shimizu, Mizuno, Nakagawa and Kuwabara receive research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan, and Kuwabara serves as an associate editor of ‘Journal of Neurology. Neurosurgery, and Psychiatry’, and as an editorial board member of ‘Journal of the Neurological Sciences’ and ‘Internal medicine’.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.