Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia
Primary Purpose
Myotonia, Non-Dystrophic Myotonia
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Mexiletine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Myotonia
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
Sites / Locations
- University of Kansas Medical Center
- Brigham & Women's Hospital
- University of Rochester School of Medicine & Dentistry
- University of Texas Southwestern Medical Center
- London Health Sciences Center
- University of Milan
- Institute of Neurology and National Hospital for Neurology
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
1
2
Arm Description
Participants will receive mexiletine for 4 weeks, then no intervention for 1 week, and finally placebo for 4 weeks.
Participants will receive placebo for 4 weeks, then no intervention for 1 week, and finally mexiletine for 4 weeks.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
Clinical Hand Grip Myotonia Evaluation (Seconds)
The time to open the fist after a forced handgrip as measured on a stopwatch.
Clinical Eye Closure Myotonia Evaluation (Seconds)
Time to open the eyes after forced eye closure as measured on a stopwatch.
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.
Compound Motor Action Potentials After Long Exercise Test
Compound muscle action potential (CMAP) after long periods of exercise as a percentage of baseline.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00832000
Brief Title
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
2. Study Status
Record Verification Date
August 2013
Overall Recruitment Status
Completed
Study Start Date
December 2008 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
March 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Richard Barohn, MD
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myotonia, Non-Dystrophic Myotonia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
59 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Description
Participants will receive mexiletine for 4 weeks, then no intervention for 1 week, and finally placebo for 4 weeks.
Arm Title
2
Arm Type
Experimental
Arm Description
Participants will receive placebo for 4 weeks, then no intervention for 1 week, and finally mexiletine for 4 weeks.
Intervention Type
Drug
Intervention Name(s)
Mexiletine
Intervention Description
200 mg three times a day; in pill form
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo three times a day; in pill form
Primary Outcome Measure Information:
Title
Patient-reported Stiffness on the IVR
Description
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.
Time Frame
Weeks 3-4 of each period
Secondary Outcome Measure Information:
Title
Patient Reported Pain on the IVR
Description
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.
Time Frame
Weeeks 3-4 of each period
Title
Patient Reported Weakness on the IVR
Description
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.
Time Frame
Weeks 3-4 of each period
Title
Patient Reported Tiredness on the IVR
Description
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.
Time Frame
Weeks 3-4 of each period
Title
Quantitative Measure of Hand Grip Myotonia (Seconds)
Description
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.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
Title
Compound Motor Action Potentials After Short Exercise Test
Description
The maximal post-exercise compound muscle action potential (CMAP) after short periods of exercise as a percent of the baseline measurement.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
Title
Graded Myotonia by Needle Electromyography - Right Abductor Digiti Minimi
Description
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.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
Title
Clinical Hand Grip Myotonia Evaluation (Seconds)
Description
The time to open the fist after a forced handgrip as measured on a stopwatch.
Time Frame
The end of period 1 (week 4) and the end of period 2 (week 9)
Title
Clinical Eye Closure Myotonia Evaluation (Seconds)
Description
Time to open the eyes after forced eye closure as measured on a stopwatch.
Time Frame
The end of period 1 (week 4) and the end of period 2 (week 9)
Title
Graded Myotonia by Needle Electromyography - Right Tibialis Anterior
Description
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.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
Title
Compound Motor Action Potentials After Long Exercise Test
Description
Compound muscle action potential (CMAP) after long periods of exercise as a percentage of baseline.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
Title
Individualized Neuromuscular Quality of Life Scale - Summary Score
Description
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.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
Title
Short Form 36 - Physical Composite Score
Description
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.
Time Frame
Particiapnts who experienced weakness on mexiletine in either period 1 or period 2.
Title
Short Form 36 - Mental Composite Score
Description
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.
Time Frame
The end of period 1 (week 4) and period 2 (week 9)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
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
Facility Information:
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Brigham & Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Rochester School of Medicine & Dentistry
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
London Health Sciences Center
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5A5
Country
Canada
Facility Name
University of Milan
City
Milan
Country
Italy
Facility Name
Institute of Neurology and National Hospital for Neurology
City
London
ZIP/Postal Code
WC1N 3BG
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
23032552
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.
Results Reference
derived
Learn more about this trial
Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia
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