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Clinical Trial
. 2021 Mar;63(3):371-383.
doi: 10.1002/mus.27146. Epub 2020 Dec 31.

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

Michael D Weiss  1 , Eric A Macklin  2 , Courtney E McIlduff  3 , Steve Vucic  4 , Brian J Wainger  5 , Matthew C Kiernan  4 , Stephen A Goutman  6 , Namita A Goyal  7 , Seward B Rutkove  3 , Shafeeq S Ladha  8 , I-Hweii Amy Chen  9 , Matthew B Harms  10 , Thomas H Brannagan  10 , David Lacomis  11 , Sasha Zivkovic  11 , Maxwell Ma  1 , Leo H Wang  1 , Zachary Simmons  12 , Michael H Rivner  13 , Jeremy M Shefner  8 , Merit E Cudkowicz  5 , Nazem Atassi  5 ; Mexiletine-2 ALS Study Group
Affiliations
Clinical Trial

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

Michael D Weiss et al. Muscle Nerve. 2021 Mar.

Abstract

Background: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.

Methods: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).

Results: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.

Conclusions: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.

Keywords: amyotrophic lateral sclerosis; axonal excitability; outcome research; randomized controlled clinical trial; transcranial magnetic stimulation.

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Conflict of interest statement

DISCLOSURES OF CONFLICTS OF INTEREST

Dr. Weiss has consulted for Ra Pharma, Argenx, and Biogen and is a speaker for NuFactor. Dr. Macklin is a DSMB member for Shire Human Genetic Therapies and for Novartis, a Steering Committee member for a Biogen trial, and on the advisory board member for Cerevance, Intrance, and Inventram, and has received research support from Amylyx Pharmaceuticals, GlaxoSmithKline, and Mitsubishi Tanabe Pharma America. Professor Vucic reports receiving funding from the National Health & Medical Research Council Australia, honoraria from CSL Australia, and serving on scientific advisory boards for Biogen and ClENE. Dr. Wainger has received personal compensation from Amgen, Quralis, Apic Biosciences, Q-State Biosciences, Takeda, and is co-inventor on a patent for the use of potassium channel openers in neurodegenerative diseases. He is a New York Stem Cell Foundation–Robertson Investigator and has received research funding from the ALS Association, GlaxoSmithKline, AI Therapeutics, Target ALS, NIH, Revalesio, and Sanofi. Dr. Goutman is on the scientific advisory for Biogen and IFT Pharma. Dr. Goyal has received research support from Brainstorm Cell Therapeutics, Cytokinetics, Fulcrum, Kezar, Novartis, Octapharma, Orion, Orphazyme, served on Advisory Boards for Acceleron, Alexion, Argenx, Biogen, CSL Behring, Cytokinetics, MT Pharma, Novartis, Sanofi Genzyme, Sarepta, and is on the speaker's bureau for CSL. Dr. Rutkove has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myolex, Biogen, Axcella Health, Merck. He has received personal compensation in an editorial capacity for Annals of Neurology and for serving on the Board of Directors of Myolex, Inc. He also holds stock and/or stock options in Myolex, Inc. Dr. Ladha reports receiving research support from the ALS Association, consulting for Biogen and Amylyx, and speaking for Biogen. Dr. Chen reports research support from the Muscular Dystrophy Association, ALS Association/ Barrow Neurological Institute, Flex Pharma, Inc., Healey ALS Center, NEALS, UCB, and consulting for Biogen. Dr. Harms has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi, and Maze Therapeutics and received research support from Biogen. Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Ionis, Akcea, Alnylam, Shire, and CSL Behring and research support from Ionis, Alnylam, Viromed, Catalyst, Pharnext, Flexpharma, Novartis, and Grifols. Dr. Lacomis reports research support from Orion Pharma, Mitsubishi-Tanabe, and the ALS Association, and royalties from UpToDate. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen and Argenx. He also holds stock and/or stock options in GWPH and Spark Therapeutics and has received research support from Fulcrum Therapeutic. Dr. Simmons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven, Biogen, Cytokinetics. He has also received personal compensation in an editorial capacity for Muscle & Nerve and research support from Biogen, Biohaven, Cytokinetics, Genzyme, and Mallinckrodt. Dr. Rivner has consulted for and received research support from Alexion and Allergan, Research support from UCB, Mallinckrodt, Cytokinetics, Momenta, Shire Takeda, Orion, Biohaven, Catalyst, Grifols, Seikagaku, and RA pharmaceuticals. Dr. Shefner has received personal compensation from Cytokinetics, Avexis, Revalasio, Biohaven, Neurosense, MTPA, and Otsuka and for serving as neuromuscular section editor for UpToDate, and research support from Cytokinetics, Biogen, Brainstorm, MTPA, and Amylyx. Dr. Cudkowicz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Takeda, Biogen, Cytokinetics, Sunovian, Immunitypharm, and Avexis. Dr. Atassi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, GSK, MT Pharma, and Neuropore Therapies. The remaining authors have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
CONSORT diagram. Mex = mexiletine.; RMT = resting motor threshold.; CMAP = compound muscle action potential
FIGURE 2
FIGURE 2
Mexiletine treatment effects on cortical excitability. Plots show treatment- and visit-specific estimates with 95% confidence bounds from a shared baseline, mixed model repeated measures analysis for: Resting motor threshold (A), MEP amplitude at 120% of RMT/ peak CMAP (B), short-interval intracortical inhibition (C), and cortical silent period (D)
FIGURE 3
FIGURE 3
Mexiletine treatment effects on axonal excitability of peripheral motor nerves. Plots show treatment- and visit-specific estimates with 95% confidence bounds from a shared baseline, mixed model repeated measures analysis for: Strength-duration time constant (A), depolarizing threshold electrotonus, 90-100 ms (B), hyperpolarizing threshold electrotonus, 90-100 ms (C), accommodation half-time (D), superexcitability (E), and subexcitability (F)
See this image and copyright information in PMC

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