Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.
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Wainger Brian J, Macklin Eric A, Vucic Steve, McIlduff Courtney E, Paganoni Sabrina, Maragakis Nicholas J, Bedlack Richard, Goyal Namita A, Rutkove Seward B, Lange Dale J, Rivner Michael H, Goutman Stephen A, Ladha Shafeeq S, Mauricio Elizabeth A, Baloh Robert H, Simmons Zachary, Pothier Lindsay, Kassis Sylvia Baedorf, La Thuong, Hall Meghan, Evora Armineuza, Klements David, Hurtado Aura, Pereira Joao D, Koh Joan, Celnik Pablo A, Chaudhry Vinay, Gable Karissa, Juel Vern C, Phielipp Nicolas, Marei Adel, Rosenquist Peter, Meehan Sean, Oskarsson Björn, Lewis Richard A, Kaur Divpreet, Kiskinis Evangelos, Woolf Clifford J, Eggan Kevin, Weiss Michael D, Berry James D, David William S, Davila-Perez Paula, Camprodon Joan A, Pascual-Leone Alvaro, Kiernan Matthew C, Shefner Jeremy M, Atassi Nazem, Cudkowicz Merit E
Аннотация
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.