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Neurology. 2016 Apr 19;86(16):1474-81. doi: 10.1212/WNL.0000000000002507. Epub 2016 Feb 24.

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

Author information

1
From the Department of Neurology (M.D.W., J.B.D.), University of Washington Medical Center, Seattle; Biostatistics Center (E.A.M.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Neurology (Z.S.), Penn State Hershey Medical Center, Hershey, PA; Department of Neurology (A.S.K., N.A., M.E.C.), Neurological Clinical Research Institute, Massachusetts General Hospital, Boston; Program in Pharmacology and Experimental Therapeutics (D.J.G.), Tufts University School of Medicine, Boston, MA; Department of Neurology (M.G., N.P.), UCLA Medical Center, Los Angeles, CA; Department of Neurology (J.S.S., C.Q., R.H.B.), University of Massachusetts Memorial Medical Center, Worcester; Department of Neurology (J.T.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (J.M.S.), Barrow Neurological Institute, Phoenix, AZ; Department of Neurology (R.J.B.), University of Kansas Medical Center, Kansas City; Department of Neurology (A.P.), Washington University Medical Center, St. Louis, MO; and Department of Neurology (A.S.), University of Iowa Hospitals and Clinics, Iowa City. mdweiss@uw.edu.
2
From the Department of Neurology (M.D.W., J.B.D.), University of Washington Medical Center, Seattle; Biostatistics Center (E.A.M.), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Neurology (Z.S.), Penn State Hershey Medical Center, Hershey, PA; Department of Neurology (A.S.K., N.A., M.E.C.), Neurological Clinical Research Institute, Massachusetts General Hospital, Boston; Program in Pharmacology and Experimental Therapeutics (D.J.G.), Tufts University School of Medicine, Boston, MA; Department of Neurology (M.G., N.P.), UCLA Medical Center, Los Angeles, CA; Department of Neurology (J.S.S., C.Q., R.H.B.), University of Massachusetts Memorial Medical Center, Worcester; Department of Neurology (J.T.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (J.M.S.), Barrow Neurological Institute, Phoenix, AZ; Department of Neurology (R.J.B.), University of Kansas Medical Center, Kansas City; Department of Neurology (A.P.), Washington University Medical Center, St. Louis, MO; and Department of Neurology (A.S.), University of Iowa Hospitals and Clinics, Iowa City.

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.

Comment in

PMID:
26911633
PMCID:
PMC4836879
DOI:
10.1212/WNL.0000000000002507
[Indexed for MEDLINE]
Free PMC Article

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