Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia

• Patient Reported Pain on the IVR [ Time Frame: Weeeks 3-4 of each period ] [ Designated as safety issue: No ]
  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 [ Time Frame: Weeks 3-4 of each period ] [ Designated as safety issue: No ]
  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 [ Time Frame: Weeks 3-4 of each period ] [ Designated as safety issue: No ]
  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) [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  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 [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  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 [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  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) [ Time Frame: The end of period 1 (week 4) and the end of period 2 (week 9) ] [ Designated as safety issue: No ]
  The time to open the fist after a forced handgrip as measured on a stopwatch.
• Clinical Eye Closure Myotonia Evaluation (Seconds) [ Time Frame: The end of period 1 (week 4) and the end of period 2 (week 9) ] [ Designated as safety issue: No ]
  Time to open the eyes after forced eye closure as measured on a stopwatch.
• Graded Myotonia by Needle Electromyography - Right Tibialis Anterior [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  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 [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  Compound muscle action potential (CMAP) after long periods of exercise as a percentage of baseline.
• Individualized Neuromuscular Quality of Life Scale - Summary Score [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  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 [ Time Frame: Particiapnts who experienced weakness on mexiletine in either period 1 or period 2. ] [ Designated as safety issue: No ]
  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 [ Time Frame: The end of period 1 (week 4) and period 2 (week 9) ] [ Designated as safety issue: No ]
  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.

• Patient-assessed pain, weakness, and fatigue [ Time Frame: Measured at Weeks 0, 4, 5, and 9 ] [ Designated as safety issue: No ]
• Clinical myotonia [ Time Frame: Measured at Weeks 0, 4, 5, and 9 ] [ Designated as safety issue: No ]
• Quality of life [ Time Frame: Measured at Weeks 0, 4, 5, and 9 ] [ Designated as safety issue: No ]
• Quantitative measure of grip myotonia [ Time Frame: Measured at Weeks 0, 4, 5, and 9 ] [ Designated as safety issue: No ]
• Compound motor action potentials after short and long exercise tests [ Time Frame: Measured at Weeks 0, 4, 5, and 9 ] [ Designated as safety issue: No ]
• Grading of myotonia on needle electromyography (EMG) [ Time Frame: Measured at Weeks 0, 4, 5, and 9 ] [ Designated as safety issue: No ]

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.

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.

• Myotonia
• Non-Dystrophic Myotonia

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

• Experimental: 1
  Participants will receive mexiletine for 4 weeks, then no intervention for 1 week, and finally placebo for 4 weeks.
  Interventions:

  • Drug: Mexiletine
  • Drug: Placebo
• Experimental: 2
  Participants will receive placebo for 4 weeks, then no intervention for 1 week, and finally mexiletine for 4 weeks.
  Interventions:

  • Drug: Mexiletine
  • Drug: Placebo

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