TY - JOUR
T1 - Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis
T2 - A Randomized Clinical Trial
AU - Wainger, Brian J.
AU - Macklin, Eric A.
AU - Vucic, Steve
AU - McIlduff, Courtney E.
AU - Paganoni, Sabrina
AU - Maragakis, Nicholas J.
AU - Bedlack, Richard
AU - Goyal, Namita A.
AU - Rutkove, Seward B.
AU - Lange, Dale J.
AU - Rivner, Michael H.
AU - Goutman, Stephen A.
AU - Ladha, Shafeeq S.
AU - Mauricio, Elizabeth A.
AU - Baloh, Robert H.
AU - Simmons, Zachary
AU - Pothier, Lindsay
AU - Kassis, Sylvia Baedorf
AU - La, Thuong
AU - Hall, Meghan
AU - Evora, Armineuza
AU - Klements, David
AU - Hurtado, Aura
AU - Pereira, Joao D.
AU - Koh, Joan
AU - Celnik, Pablo A.
AU - Chaudhry, Vinay
AU - Gable, Karissa
AU - Juel, Vern C.
AU - Phielipp, Nicolas
AU - Marei, Adel
AU - Rosenquist, Peter
AU - Meehan, Sean
AU - Oskarsson, Björn
AU - Lewis, Richard A.
AU - Kaur, Divpreet
AU - Kiskinis, Evangelos
AU - Woolf, Clifford J.
AU - Eggan, Kevin
AU - Weiss, Michael D.
AU - Berry, James D.
AU - David, William S.
AU - Davila-Perez, Paula
AU - Camprodon, Joan A.
AU - Pascual-Leone, Alvaro
AU - Kiernan, Matthew C.
AU - Shefner, Jeremy M.
AU - Atassi, Nazem
AU - Cudkowicz, Merit E.
N1 - Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - 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-1was 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-1increased 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-1did 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.
AB - 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-1was 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-1increased 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-1did 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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U2 - 10.1001/jamaneurol.2020.4300
DO - 10.1001/jamaneurol.2020.4300
M3 - Article
C2 - 33226425
AN - SCOPUS:85096658364
SN - 2168-6149
VL - 78
SP - 186
EP - 196
JO - JAMA neurology
JF - JAMA neurology
IS - 2
ER -