Document Detail


Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.
MedLine Citation:
PMID:  23032552     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CONTEXT: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible.
OBJECTIVE: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network.
INTERVENTION: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between.
MAIN OUTCOME MEASURES: Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact).
RESULTS: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related.
CONCLUSION: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00832000.
Authors:
Jeffrey M Statland; Brian N Bundy; Yunxia Wang; Dipa Raja Rayan; Jaya R Trivedi; Valeria A Sansone; Mohammad K Salajegheh; Shannon L Venance; Emma Ciafaloni; Emma Matthews; Giovanni Meola; Laura Herbelin; Robert C Griggs; Richard J Barohn; Michael G Hanna;
Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  JAMA : the journal of the American Medical Association     Volume:  308     ISSN:  1538-3598     ISO Abbreviation:  JAMA     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-03     Completed Date:  2012-10-09     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7501160     Medline TA:  JAMA     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1357-65     Citation Subset:  AIM; IM    
Affiliation:
Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00832000
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Adolescent
Adult
Aged
Anti-Arrhythmia Agents / adverse effects,  therapeutic use*
Cross-Over Studies
Double-Blind Method
Female
Humans
Male
Mexiletine / adverse effects,  therapeutic use*
Middle Aged
Muscle, Skeletal / physiopathology
Myotonia / drug therapy*
Pain / drug therapy,  etiology
Quality of Life
Severity of Illness Index
Sodium Channels / drug effects
Young Adult
Grant Support
ID/Acronym/Agency:
R01 FD 003454/FD/FDA HHS; T32 NS07338-20/NS/NINDS NIH HHS; U54 NS059065-05S1/NS/NINDS NIH HHS; UL1 RR 024160/RR/NCRR NIH HHS; UL1 RR 024982/RR/NCRR NIH HHS; UL1 RR 033179/RR/NCRR NIH HHS; UL1 RR024160/RR/NCRR NIH HHS; UL1 RR033179/RR/NCRR NIH HHS; UL1 TR 000001/TR/NCATS NIH HHS; UL1 TR000001/TR/NCATS NIH HHS; //Medical Research Council
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Sodium Channels; 31828-71-4/Mexiletine
Investigator
Investigator/Affiliation:
Richard J Barohn / ; Yunxia Wang / ; Jeffrey Statland / ; Mazen Dimachkie / ; Laura Herbelin / ; JoAnn Miller / ; Rhea Pimental / ; Jaya Trivedi / ; Nina Gorham / ; Rhonda McLin / ; Vivian Gonzales / ; Mohammad Kian Salajegheh / ; Anthony A Amato / ; Kristen Roe / ; Samantha Chused / ; Essa Kayd / ; Shannon Venance / ; Angelica Hahn / ; Wilma Koopman / ; Jennifer Verheyden / ; Ashley Ten Haaf / ; Christine Piechowicz / ; Robert C Griggs / ; Emma Ciafaloni / ; Paul Twydell / ; Katherine Aronson / ; Kimberly Hart / ; Patricia Smith / ; Barbara Herr / ; Kate Eichinger / ; Shree Pandya / ; Stephen Bean / ; Araya Puwanant / ; Quing Ke / ; Jill Scheltz / ; Laura Whitesell / ; Michael Hanna / ; Dipa L Raja Rayan / ; Emma Matthews / ; Gisela Barreto / ; Veronica Tan / ; James Burge / ; Elizabeth Dewar / ; Daleen Lopez-Begum / ; Richa Sud / ; Andrea Haworth / ; Samuel McCall / ; Valeria Sansone / ; Giovanni Meola / ; Alice Zanolini / ; Matteo Ciocca / ; Brian Bundy / ; Jeffrey Krischer / ; Holly Ruhlig / ; Joseph Gomes / ; Rachel Richesson / ; Renee Leduc / ; Jennifer Pilger / ; John W Day / ; Robert T Leshner / ; Todd A Mackenzie / ; Kathryn Wagner / ; Joanne C Odenkirchen / ; Randy Stewart /
Comments/Corrections
Comment In:
JAMA. 2012 Oct 3;308(13):1377-8   [PMID:  23032555 ]

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