Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia

Non-Dystrophic Myotonia Clinical Trial

Official title:

Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00832000
• Other study ID #: 11050
• Secondary ID: FDA OPD RO1FD003
• Status: Completed
• Phase: Phase 2
• First received: January 27, 2009
• Last updated: August 19, 2013
• Start date: December 2008
• Est. completion date: March 2011

Study information

• Verified date: August 2013
• Source: University of Kansas Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00721942

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: March 2011
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Myotonia
• Non-Dystrophic Myotonia

Intervention

Drug:
• Mexiletine
200 mg three times a day; in pill form
• Placebo
Placebo three times a day; in pill form

Locations

Country	Name	City	State
Canada	London Health Sciences Center	London	Ontario
Italy	University of Milan	Milan
United Kingdom	Institute of Neurology and National Hospital for Neurology	London
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Rochester School of Medicine & Dentistry	Rochester	New York

Sponsors (1)

Lead Sponsor	Collaborator
Richard Barohn, MD

Countries where clinical trial is conducted

United States,  Canada,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Patient-reported Stiffness on the IVR	Stiffness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of stiffness for each participant was calculated from daily calls made in weeks 3-4 of each period.	Weeks 3-4 of each period	No
Secondary	Patient Reported Pain on the IVR	Pain measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of pain for each participant was calculated from daily calls made in weeks 3-4 of each period.	Weeeks 3-4 of each period	No
Secondary	Patient Reported Weakness on the IVR	Weakness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of weakness for each participant was calculated from daily calls made in weeks 3-4 of each period.	Weeks 3-4 of each period	No
Secondary	Patient Reported Tiredness on the IVR	Tiredness measured on a 1-9 scale, 1 being minimal, 9 the worst ever experienced. 0=no symptom reported. For analysis the average severity of tiredness for each participant was calculated from daily calls made in weeks 3-4 of each period.	Weeks 3-4 of each period	No
Secondary	Quantitative Measure of Hand Grip Myotonia (Seconds)	Maximum voluntary contractions following forced right hand grip were recorded and the time to relax from 90% to 5% of average maximal force was determined using automated analysis software.	The end of period 1 (week 4) and period 2 (week 9)	No
Secondary	Compound Motor Action Potentials After Short Exercise Test	The maximal post-exercise compound muscle action potential (CMAP) after short periods of exercise as a percent of the baseline measurement.	The end of period 1 (week 4) and period 2 (week 9)	No
Secondary	Graded Myotonia by Needle Electromyography - Right Abductor Digiti Minimi	Measured the amount of myotonia present on needle exam by assigning a number 1-3, with 1 being minimal amount of myotonia on needle stick and 3 being maximal amount of myotonia present on needle stick.	The end of period 1 (week 4) and period 2 (week 9)	No
Secondary	Clinical Hand Grip Myotonia Evaluation (Seconds)	The time to open the fist after a forced handgrip as measured on a stopwatch.	The end of period 1 (week 4) and the end of period 2 (week 9)	No
Secondary	Clinical Eye Closure Myotonia Evaluation (Seconds)	Time to open the eyes after forced eye closure as measured on a stopwatch.	The end of period 1 (week 4) and the end of period 2 (week 9)	No
Secondary	Graded Myotonia by Needle Electromyography - Right Tibialis Anterior	Measured the amount of myotonia present on needle exam by assigning a number 1-3, with 1 being minimal amount of myotonia on needle stick and 3 being maximal amount of myotonia present on needle stick.	The end of period 1 (week 4) and period 2 (week 9)	No
Secondary	Compound Motor Action Potentials After Long Exercise Test	Compound muscle action potential (CMAP) after long periods of exercise as a percentage of baseline.	The end of period 1 (week 4) and period 2 (week 9)	No
Secondary	Individualized Neuromuscular Quality of Life Scale - Summary Score	Quality of life scale for patinets with neuromuscular disorders. The INQoL summary score is a weighted average made up of 5 subdomains (activities, social relationships, independence, emotions, and body image) which document the impact of a disease on a patients' quality of life. Scores range from 0-100, and can be interpreted as the percent of maximal detrimental impact on quality of life. A higher score indicates more detrimental impact.	The end of period 1 (week 4) and period 2 (week 9)	No
Secondary	Short Form 36 - Physical Composite Score	The SF-36 is a standard quality of life instrument. The physical composite score represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). The score is nomralized to the population and ranges from 0-100, with the US normal value of 50. A lower score represents a greater impact of quality of life.	Particiapnts who experienced weakness on mexiletine in either period 1 or period 2.	No
Secondary	Short Form 36 - Mental Composite Score	The SF-36 is a standard quality of life instrument. The mental composite score represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). The score is nomralized to the population and ranges from 0-100, with the US normal value of 50. A lower score represents a greater impact of quality of life.	The end of period 1 (week 4) and period 2 (week 9)	No