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Original Investigation
November 23, 2020

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Author Affiliations
  • 1The Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Boston
  • 2Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, Boston
  • 3Harvard Medical School, Boston MA
  • 4Harvard Stem Cell Institute, Cambridge
  • 5Broad Institute of MIT and Harvard, Cambridge
  • 6Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts
  • 7Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia
  • 8Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 9Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, Massachusetts
  • 10Department of Neurology, Johns Hopkins University, Baltimore, Maryland
  • 11Department of Neurology, Duke University Medical Center, Durham, North Carolina
  • 12Department of Neurology, University of California Irvine, Irvine
  • 13Department of Neurology, Hospital for Special Surgery, New York, New York
  • 14Department of Neurology, Augusta University Medical Center, Augusta, Georgia
  • 15Department of Neurology, University of Michigan, Ann Arbor
  • 16Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona
  • 17Department of Neurology, Mayo Clinic, Jacksonville, Florida
  • 18Department of Neurology, Cedars Sinai Medical Center, Los Angeles, California
  • 19Department of Neurology, Penn State Hershey Medical Center, Hershey, Pennsylvania
  • 20Department of Psychiatry, Massachusetts General Hospital, Boston
  • 21Department of Psychiatry, Augusta University Medical Center, Augusta, Georgia
  • 22School of Kinesiology, University of Michigan, Ann Arbor
  • 23Department of Neurology, Northwestern University, Chicago, Illinois
  • 24Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts
  • 25Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts
  • 26Department of Neurology, University of Washington, Seattle
  • 27Marcus Institute and Center for Memory Health, Hebrew SeniorLife, Boston, Massachusetts
  • 28Institut Guttmann, Universitat Autonoma, Barcelona, Spain
  • 29Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia
  • 30Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
JAMA Neurol. 2021;78(2):186-196. doi:10.1001/jamaneurol.2020.4300
Key Points

Question  Can ezogabine reduce cortical and spinal motor neuron excitability, which are increased in amyotrophic lateral sclerosis (ALS)?

Findings  In this randomized clinical trial of 65 participants with ALS, treatment with ezogabine reduced both cortical and spinal motor neuron excitability in a dose-dependent manner.

Meaning  This trial found that ezogabine decreased excitability in ALS; further evaluation is warranted to determine whether longer treatment can sustain the effects on excitability and slow disease progression.


Importance  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.

Objective  To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.

Design, Setting, and Participants  This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.

Interventions  Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.

Main Outcomes and Measures  The primary outcome was change in short-interval intracortical inhibition (SICI; SICI−1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.

Results  A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI−1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI−1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).

Conclusions and Relevance  Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

Trial Registration  ClinicalTrials.gov Identifier: NCT02450552

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