Clinical Efficacy Trial of Mexiletine for Myotonic Dystrophy Type 1

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effects of mexiletine treatment for 6 months on ambulation, myotonia, muscle function and strength, pain, gastrointestinal functioning, cardiac conduction, and quality of life in myotonic dystrophy type 1 (DM1).

Detailed Description
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This study will provide data on the long term (6 months) safety and efficacy of mexiletine in: improving the distance participants are able to walk in six minutes; reducing myotonia; improving muscle strength; increasing lean muscle mass; decreasing musculoskeletal pain; improving gastrointestinal function and swallowing); improving functional abilities; decreasing cardiac arrhythmias; and improving disease-specific health related quality-of-life.

Official Title
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A Randomized, Placebo Controlled, Clinical Efficacy Trial of Mexiletine for Myotonic Dystrophy Type-1 (DM1)

Conditions
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Myotonic Dystrophy

Intervention / Treatment
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* Drug: Mexiletine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of DM1, confirmed by DM1 genetic mutation Ability to walk 30 feet (assistance with cane and/or leg bracing permitted) Presence of grip myotonia Exclusion Criteria: Congenital DM1 Treatment with Mexiletine within past 8 weeks Second or third degree heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, or is receiving medication for treatment of a cardiac arrhythmia Receiving another antimyotonia drug Liver or kidney disease requiring ongoing treatment Has a seizure disorder Is pregnant or lactating Had severe depression within 3 months or a history of suicide ideation Has any one of the following medical conditions: uncontrolled diabetes mellitus, congestive heart failure, symptomatic cardiomyopathy, symptomatic coronary artery disease, cancer (other than skin cancer) less than five years previously, multiple sclerosis, or other serious medical illness. Drug or alcohol abuse within 3 months Coexistence of another neuromuscular disease Is unable to give informed consent Severe arthritis or other medical condition (besides DM1) that would significantly impact ambulation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mexiletine<br>20 subjects will be randomized (assigned) to receive Mexiletine. Mexiletine is available on the market for the treatment of cardiac arrhythmias, but it is not currently approved for the treatment of myotonia or myotonic dystrophy. | Drug: Mexiletine<br>* 150 mg/kg Mexiletine capsules taken by mouth, three times daily for 6 months<br>* Other names: Generic name: mexiletine hydrochloride;|
| Placebo Comparator: Sugar pill<br>20 subjects will be randomized (assigned) to receive placebo (sugar pill). This control group is necessary to definitely establish the antimyotonic efficacy and safety of mexiletine. | Drug: Placebo<br>* 150 mg/kg placebo capsules taken by mouth, three times daily for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Ambulation Using the 6 Minute Walk Distance | During this assessment, participants were asked to walk as far as they could back and forth on a fixed 20 meter route for 6 minutes. The total distance walked during the 6 minutes was recorded in meters. Change from baseline was defined as the difference between the average 6 minute walk distance at baseline and the average 6 minute walk distance at 6 months. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Had a Dose Reduction or a Study Drug Withdrawal or Suspension Over 6 Months | Adverse events were monitored at the three in-person evaluations (Months 0, 3, and 6), at telephone evaluations every 2 weeks, and via patient-completed side effect diaries. The study investigators and safety monitoring committee reviewed adverse events and made decisions regarding drug withdrawals, suspensions, and dose reductions as needed. | 6 months | 
| Mean Change From Baseline in Quantitative Measure of Hand Grip Myotonia | Relaxation time of the long finger flexor muscles of the right hand after a maximum voluntary isometric contraction performed in a standardized fixed position of the right arm elbow/wrist/hand. Relaxation time for this measurement is defined as the time to relax from 90% to 5% of the maximum isometric force of contraction of the hand (the first of 6 serial contractions averaged over two consecutive trials performed 10 minutes apart). | Baseline to 6 months | 
| Mean Change From Baseline in Manual Muscle Testing (MMT) Score | Manual muscle testing was performed on 26 muscle groups (shoulder abductors, elbow flexors, wrist flexors, wrist extensors, hip flexors, knee extensors, hip extensors, knee flexors, hip abductors, elbow extensors, ankle dorsiflexors, and plantar flexors on the right and left plus neck extensor and neck flexors). The muscles were tested in various positions including sitting, supine, prone, and side lying and each graded on a modification of the Medical Research Council (MRC) scale of 0 to 5 (5 representing normal strength). Average MMT score is derived by averaging the individual MMT scores across the 26 individual muscles. | Baseline to 6 months | 
| Mean Change From Baseline in PR, QRS, and QTc Intervals, and Average Minimum Heart Rate (HR) Via Electrocardiogram (ECG) Monitoring | PR, QRS, and QTc intervals as well as average minimum heart rate (HR) were obtained through standard 12 lead electrocardiograms (ECGs). Values were computer generated and verified by the study investigator and study cardiologist. | Baseline to 6 Months | 
| Mean Change From Baseline in Patient-Reported Disease Burden and Quality of Life | The Myotonic Dystrophy Health Index (MDHI) is a validated disease-specific measure of patient-reported disease burden. The MDHI total score is a weighted average derived from 17 subscales. MDHI total scores range form 0-100 with 0 representing no patient-reported disease burden and 100 representing the most severe patient-reported disease burden. The Individualized Neuromuscular Quality of Life Questionnaire (INQoL) is a measure of quality of life in neuromuscular disease. The INQoL summary score is a weighted average made up of 5 sub-domains. Scores range from 0-100, and can be interpreted as the percent of maximal detrimental impact on quality of life with higher scores indicating more detrimental impact. The 36-Item Short Form Survey (SF-36) is a generic measure of quality of life across 8 domains. Two summary metrics are produced from the 8 domains, ranging from 0-100% with lower scores representing worse levels of functioning. | Baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myotonic Dystrophy, Myotonic Dystrophy Type 1 (DM1), Muscular Dystrophy, Mexiletine