A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression.

Abstract

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.

• Authors: 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 Jr, Jane B Distad, Jaya Trivedi, Jeremy M Shefner, Richard J Barohn, Alan Pestronk, Andrea Swenson, Merit E Cudkowicz, Mexiletine ALS Study Group
• Journal: Neurology (Neurology) Vol. 86 Issue 16 Pg. 1474-81 (Apr 19 2016) ISSN: 1526-632X [Electronic] United States
• PMID: 26911633 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: © 2016 American Academy of Neurology.

Chemical References

• Voltage-Gated Sodium Channel Blockers
• Mexiletine

Topics

• Amyotrophic Lateral Sclerosis (drug therapy, physiopathology)
• Disease Progression
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Male
• Mexiletine (adverse effects, pharmacokinetics, therapeutic use)
• Middle Aged
• Muscle Cramp (drug therapy, physiopathology)
• Postural Balance (drug effects)
• Treatment Outcome
• Voltage-Gated Sodium Channel Blockers (adverse effects, pharmacokinetics, therapeutic use)