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著者: 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, Mexiletine ALS Study Group
雑誌名: Neurology. 2016 Apr 19;86(16):1474-81. doi: 10.1212/WNL.0000000000002507. Epub 2016 Feb 24.
Abstract/Text
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.
© 2016 American Academy of Neurology.
PMID 26911633 Neurology. 2016 Apr 19;86(16):1474-81. doi: 10.1212/WNL.0000000000002507. Epub 2016 Feb 24.
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