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 journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1474-1481
Number of pages8
JournalNeurology
Volume86
Issue number16
DOIs
StatePublished - Apr 19 2016

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Mexiletine
Muscle Cramp
Placebos
Vital Capacity
Pharmacokinetics
Safety
Amyotrophic Lateral Sclerosis
Randomized Controlled Trials

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Weiss, M. D., Macklin, E. A., Simmons, Z., Knox, A. S., Greenblatt, D. J., Atassi, N., ... Cudkowicz, M. E. (2016). A randomized trial of mexiletine in ALS. Neurology, 86(16), 1474-1481. https://doi.org/10.1212/WNL.0000000000002507
Weiss, Michael D. ; Macklin, Eric A. ; Simmons, Zachary ; Knox, Angela S. ; Greenblatt, David J. ; Atassi, Nazem ; Graves, Michael ; Parziale, Nicholas ; Salameh, Johnny S. ; Quinn, Colin ; Brown, Robert H. ; Distad, Jane B. ; Trivedi, Jaya ; Shefner, Jeremy M. ; Barohn, Richard J. ; Pestronk, Alan ; Swenson, Andrea ; Cudkowicz, Merit E. / A randomized trial of mexiletine in ALS. In: Neurology. 2016 ; Vol. 86, No. 16. pp. 1474-1481.
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title = "A randomized trial of mexiletine in ALS",
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.",
author = "Weiss, {Michael D.} and Macklin, {Eric A.} and Zachary Simmons and Knox, {Angela S.} and Greenblatt, {David J.} and Nazem Atassi and Michael Graves and Nicholas Parziale and Salameh, {Johnny S.} and Colin Quinn and Brown, {Robert H.} and Distad, {Jane B.} and Jaya Trivedi and Shefner, {Jeremy M.} and Barohn, {Richard J.} and Alan Pestronk and Andrea Swenson and Cudkowicz, {Merit E.}",
year = "2016",
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Weiss, MD, Macklin, EA, Simmons, Z, Knox, AS, Greenblatt, DJ, Atassi, N, Graves, M, Parziale, N, Salameh, JS, Quinn, C, Brown, RH, Distad, JB, Trivedi, J, Shefner, JM, Barohn, RJ, Pestronk, A, Swenson, A & Cudkowicz, ME 2016, 'A randomized trial of mexiletine in ALS', Neurology, vol. 86, no. 16, pp. 1474-1481. https://doi.org/10.1212/WNL.0000000000002507

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

In: Neurology, Vol. 86, No. 16, 19.04.2016, p. 1474-1481.

Research output: Contribution to journalArticle

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T1 - A randomized trial of mexiletine in ALS

AU - Weiss, Michael D.

AU - Macklin, Eric A.

AU - Simmons, Zachary

AU - Knox, Angela S.

AU - Greenblatt, David J.

AU - Atassi, Nazem

AU - Graves, Michael

AU - Parziale, Nicholas

AU - Salameh, Johnny S.

AU - Quinn, Colin

AU - Brown, Robert H.

AU - Distad, Jane B.

AU - Trivedi, Jaya

AU - Shefner, Jeremy M.

AU - Barohn, Richard J.

AU - Pestronk, Alan

AU - Swenson, Andrea

AU - Cudkowicz, Merit E.

PY - 2016/4/19

Y1 - 2016/4/19

N2 - 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.

AB - 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.

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Weiss MD, Macklin EA, Simmons Z, Knox AS, Greenblatt DJ, Atassi N et al. A randomized trial of mexiletine in ALS. Neurology. 2016 Apr 19;86(16):1474-1481. https://doi.org/10.1212/WNL.0000000000002507