Clinical trial NCT00832000: Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia
Official title: Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myotonia
Non-Dystrophic Myotonia
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
First posted: 2009-01-29
Enrollment: 59
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Nondystrophic myotonias (NDM) are neuromuscular disorders caused by genetic abnormalities in certain muscle cell membrane proteins. The proteins affect muscle contraction. Individuals with NDM experience limited muscle relaxation, which then can cause pain, weakness, incoordination, and impaired physical activity and function. Because NDM is very rare, information on the best way to treat people with the disorders is lacking, and there are no FDA-approved therapies. The purpose of this study is to determine the effectiveness of the medication mexiletine in treating people with NDM.

Detailed description: NDM are neuromuscular disorders that are caused by mutations in skeletal muscle ion channels, usually voltage-dependent sodium and chloride channels. The poorly functioning channels result in impaired muscle relaxation after contraction, which is also called myotonia. Mexiletine is an antiarrhythmic medication that has a high affinity for muscle sodium channels and may have the ability to correct delayed inactivation of sodium channels. In case reports and single-blind clinical trials, mexiletine was shown to reduce symptoms of myotonia. Currently, there is no standard strategy for treating people with NDM, and effective treatment options are needed. This study will determine the effectiveness of mexiletine in treating people with NDM.

Participation in this study will last 9 weeks and will involve two separate 4-week treatment periods, with a 1-week washout period between them. During the first treatment period, participants will be randomly assigned to receive either mexiletine or placebo, both of which will be taken three times a day. This will be followed by 1 week of no treatment. During the second treatment period, participants will receive whichever treatment they did not receive initially and will follow the same dosing schedule.

Participants will attend five study visits that will occur at screening and Weeks 0, 4, 5, and 9. Screening will include blood and urine sampling, electrocardiography (EKG), and a medical history. The remaining visits will include a physical examination, a grip test, exercise tests, nerve conduction tests, blood sampling, questionnaires, and electromyography (EMG). EKG will be repeated at Weeks 4, 5, and 9. Throughout the study, participants will phone in daily to report their symptoms. There will be no follow-up visits.

Funded by FDAOPD RO1 0003454.

Eligibility criteria: Inclusion Criteria:

* Clinical symptoms or signs suggestive of myotonic disorders
* Presence of myotonic potentials on electromyography (EMG)
* Participant in the Non-Dystrophic Natural History study (RDCRN 5303) or a new patient with confirmed non-dystrophic myotonia

Exclusion Criteria:

* Other neurological condition that might affect the assessment of the study measurements
* Genetic confirmation of DM1 (more than 50 repeats of CTG) or DM2
* Existing cardiac conduction defects, as evidenced on EKG, including but not limited to the following conditions: malignant arrhythmia or cardiac conduction disturbances (e.g., second degree AV block, third degree AV block, or prolonged QT interval)
* Existing permanent pacemaker
* Current use of any of the following antiarrhythmic medications for a cardiac disorder: flecainide acetate, encainide, disopyramide, procainamide, quinidine, propafenone, or mexiletine
* Use of medications for myotonia, such as phenytoin and flecainide acetate, within 5 days of study entry; carbamazepine and mexiletine within 3 days of study entry; or propafenone, procainamide, disopyramide, quinidine, and encainide within 2 days of study entry
* Use of medications that produce myotonia, which may include fibrate acid derivatives, hydroxymethylglutaryl CoA reductase inhibitors, chloroquine, and colchicines
* Kidney or liver disease
* Heart failure
* Seizure disorder
* Pregnant or breastfeeding

Primary outcomes:
measure: Patient-reported Stiffness on the IVR
timeFrame: Weeks 3-4 of each period
Secondary outcomes:
measure: Patient Reported Pain on the IVR
timeFrame: Weeeks 3-4 of each period
measure: Patient Reported Weakness on the IVR
timeFrame: Weeks 3-4 of each period
measure: Patient Reported Tiredness on the IVR
timeFrame: Weeks 3-4 of each period
measure: Quantitative Measure of Hand Grip Myotonia (Seconds)
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
measure: Compound Motor Action Potentials After Short Exercise Test
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
measure: Graded Myotonia by Needle Electromyography - Right Abductor Digiti Minimi
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
measure: Clinical Hand Grip Myotonia Evaluation (Seconds)
timeFrame: The end of period 1 (week 4) and the end of period 2 (week 9)
measure: Clinical Eye Closure Myotonia Evaluation (Seconds)
timeFrame: The end of period 1 (week 4) and the end of period 2 (week 9)
measure: Graded Myotonia by Needle Electromyography - Right Tibialis Anterior
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
measure: Compound Motor Action Potentials After Long Exercise Test
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
measure: Individualized Neuromuscular Quality of Life Scale - Summary Score
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
measure: Short Form 36 - Physical Composite Score
timeFrame: Particiapnts who experienced weakness on mexiletine in either period 1 or period 2.
measure: Short Form 36 - Mental Composite Score
timeFrame: The end of period 1 (week 4) and period 2 (week 9)
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: University of Rochester School of Medicine & Dentistry
state: New York
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Milan
country: Italy
facility: University of Milan
city: London
country: United Kingdom
facility: Institute of Neurology and National Hospital for Neurology
Study officials:
References:
citation: Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, Salajegheh MK, Venance SL, Ciafaloni E, Matthews E, Meola G, Herbelin L, Griggs RC, Barohn RJ, Hanna MG; Consortium for Clinical Investigation of Neurologic Channelopathies. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA. 2012 Oct 3;308(13):1357-65. doi: 10.1001/jama.2012.12607.