A randomized trial of mexiletine in ALS

Michael D. Weiss, Eric A. Macklin, Zachary Simmons, Angela S. Knox, David J. Greenblatt, Nazem Atassi, Michael Graves, Nicholas Parziale, Johnny S. Salameh, Colin Quinn, Robert H. Brown, Jane B. Distad, Jaya Trivedi, Jeremy M. Shefner, Richard J. Barohn, Alan Pestronk, Andrea Swenson, Merit E. Cudkowicz

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Objective: To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS). Methods: Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity. Results: The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p < 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate 31% of placebo, p 0.047; 900 mg: 16% of placebo, p 0.002) and cramp intensity (300 mg: mean 45% of placebo, p 0.08; 900 mg: 25% of placebo, p 0.005). Conclusions: Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study. Classification of evidence: This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.

Original languageEnglish (US)
Pages (from-to)1474-1481
Number of pages8
Issue number16
StatePublished - Apr 19 2016

All Science Journal Classification (ASJC) codes

  • Clinical Neurology


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