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April 19, 2016; 86 (16) Article

A randomized trial of mexiletine in ALS

Safety and effects on muscle cramps and progression

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, For the Mexiletine ALS Study Group
First published February 24, 2016, DOI: https://doi.org/10.1212/WNL.0000000000002507
Michael D. Weiss
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.
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Eric A. Macklin
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.
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Zachary Simmons
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.
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Angela S. Knox
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.
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David J. Greenblatt
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.
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Nazem Atassi
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.
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Michael Graves
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.
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Nicholas Parziale
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.
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Johnny S. Salameh
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.
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Colin Quinn
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.
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Robert H. Brown Jr
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.
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Jane B. Distad
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.
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Jaya Trivedi
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.
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Jeremy M. Shefner
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.
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Richard J. Barohn
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.
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Alan Pestronk
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.
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Andrea Swenson
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.
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Merit E. Cudkowicz
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.
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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.
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Citation
A randomized trial of mexiletine in ALS
Safety and effects on muscle cramps and progression
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, For the Mexiletine ALS Study Group
Neurology Apr 2016, 86 (16) 1474-1481; DOI: 10.1212/WNL.0000000000002507

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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.

GLOSSARY

AE=
adverse event;
ALS=
amyotrophic lateral sclerosis;
ALSFRS-R=
revised ALS Functional Rating Scale;
AUC=
area under the concentration curve;
DSMB=
data safety monitoring board;
SAE=
serious adverse event;
SALS=
sporadic amyotrophic lateral sclerosis;
SF-36=
Short Form–36 Health Survey;
SVC=
slow vital capacity

Footnotes

  • Coinvestigators are listed on the Neurology® Web site at Neurology.org.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 1468

  • Supplemental data at Neurology.org

  • Received May 3, 2015.
  • Accepted in final form October 26, 2015.
  • © 2016 American Academy of Neurology
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