Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia

• Sponsor: Richard Barohn, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00832000
• Collaborator: (none)
• Enrollment: 59
• Locations: 7
• Arms: 2
• Duration (Months): 26.9
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Myotonia; Non-Dystrophic Myotonia	Drug: Mexiletine; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants will receive mexiletine for 4 weeks, then no intervention for 1 week, and finally placebo for 4 weeks.	Drug: Mexiletine; 200 mg three times a day; in pill form; Drug: Placebo; Placebo three times a day; in pill form
Experimental: 2 Participants will receive placebo for 4 weeks, then no intervention for 1 week, and finally mexiletine for 4 weeks.	Drug: Mexiletine; 200 mg three times a day; in pill form; Drug: Placebo; Placebo three times a day; in pill form

Outcome Measures

Primary Outcome Measures

1. Patient-reported Stiffness on the IVR [Weeks 3-4 of each period]

   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

1. Patient Reported Pain on the IVR [Weeeks 3-4 of each period]

   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.

2. Patient Reported Weakness on the IVR [Weeks 3-4 of each period]

   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.

3. Patient Reported Tiredness on the IVR [Weeks 3-4 of each period]

   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.

4. Quantitative Measure of Hand Grip Myotonia (Seconds) [The end of period 1 (week 4) and period 2 (week 9)]

   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.

5. Compound Motor Action Potentials After Short Exercise Test [The end of period 1 (week 4) and period 2 (week 9)]

   The maximal post-exercise compound muscle action potential (CMAP) after short periods of exercise as a percent of the baseline measurement.

6. Graded Myotonia by Needle Electromyography - Right Abductor Digiti Minimi [The end of period 1 (week 4) and period 2 (week 9)]

   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.

7. Clinical Hand Grip Myotonia Evaluation (Seconds) [The end of period 1 (week 4) and the end of period 2 (week 9)]

   The time to open the fist after a forced handgrip as measured on a stopwatch.

8. Clinical Eye Closure Myotonia Evaluation (Seconds) [The end of period 1 (week 4) and the end of period 2 (week 9)]

   Time to open the eyes after forced eye closure as measured on a stopwatch.

9. Graded Myotonia by Needle Electromyography - Right Tibialis Anterior [The end of period 1 (week 4) and period 2 (week 9)]

   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.

10. Compound Motor Action Potentials After Long Exercise Test [The end of period 1 (week 4) and period 2 (week 9)]

    Compound muscle action potential (CMAP) after long periods of exercise as a percentage of baseline.

11. Individualized Neuromuscular Quality of Life Scale - Summary Score [The end of period 1 (week 4) and period 2 (week 9)]

    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.

12. Short Form 36 - Physical Composite Score [Particiapnts who experienced weakness on mexiletine in either period 1 or period 2.]

    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.

13. Short Form 36 - Mental Composite Score [The end of period 1 (week 4) and period 2 (week 9)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
2	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
3	University of Rochester School of Medicine & Dentistry	Rochester	New York	United States	14642
4	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
5	London Health Sciences Center	London	Ontario	Canada	N6A 5A5
6	University of Milan	Milan		Italy
7	Institute of Neurology and National Hospital for Neurology	London		United Kingdom	WC1N 3BG

Sponsors and Collaborators

• Richard Barohn, MD

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Richard Barohn, MD, Gertrude and Dewey Zeigler Professor of Neurology and Chair, University of Kansas Medical Center
• ClinicalTrials.gov Identifier: NCT00832000
• Other Study ID Numbers: 11050; FDA OPD RO1FD003454; NCT00721942
• First Posted: Jan 29, 2009
• Last Update Posted: Aug 23, 2013
• Last Verified: Aug 1, 2013

• Additional relevant MeSH terms: Myotonia; Mexiletine

Study Results

Participant Flow

Recruitment Details	Eligible participants were at least 16 years of age, had clinical symptoms or signs of NDM, and myotonic potentials on electromyography. Participants were either enrolled in the CINCH NDM Natural History Study, or a new patient with genetically confirmed NDM, or with clinical features of NDM but negative myotonic dystrophy DNA testing.
Pre-assignment Detail	Patients taking anti-myotonic agents were required to discontinue medications for a wash-out period equal to 7 times the half-life of elimination prior to their baseline visit. Participants were ineligible if they has specific contraindications to taking mexiletine (cardiac conduction defects, hepatic or renal disease, or heart failure).

Arm/Group Title	Mexiletine Then Placebo	Placebo Then Mexiletine
Arm/Group Description	29 Participants will receive mexiletine for 4 weeks, then no intervention for 1 week, and finally placebo for 4 weeks. Included in anaysis*: 28 patients *Modified intention to treat analysis. 1 subject in each group not included in primary analysis due to failure to make any calls to the IVR system for stiffness in either period	30 Participants will receive placebo for 4 weeks, then no intervention for 1 week, and finally mexiletine for 4 weeks. Included in analysis* 29 patients *Modified intention to treat analysis. 1 subject in each not included in primary analysis due to failure to make any calls to the IVR system for stiffness in either period.
Period Title: Overall Study
STARTED	29	30
Crossed Over to Opposite Intervention	25	29
COMPLETED	23	29
NOT COMPLETED	6	1

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All participants received all inerventions; therefore, we combined all participants into one Arm/Group.
Overall Participants	59
Age (Count of Participants)
<=18 years	1 1.7%
Between 18 and 65 years	56 94.9%
>=65 years	2 3.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.9 (25)
Sex: Female, Male (Count of Participants)
Female	26 44.1%
Male	33 55.9%
Region of Enrollment (participants) [Number]
United States	31 52.5%
Canada	4 6.8%
United Kingdom	12 20.3%
Italy	12 20.3%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Modified intention to treat analysis (n=57). 2 subjects were excluded from analysis due to failure call the IVR system in either period. Treatment group estimates by period are taken from the mixed model, the number above reflecting the number who contributed to the model point estimate. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine - Period 1	Placebo - Period 1	Mexiletine - Period 2	Placebo - Period 2
Arm/Group Description	Mexiletine capsules 200 mg orally three times daily period 1. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.	Placebo capsules orally three times dailyperiod 1. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.	Mexiletine capsules 200 mg orally three times daily period 2. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.	Placebo capsules orally three times dailyperiod 2. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.
Measure Participants	28	29	29	25
Mean (95% Confidence Interval) [units on a scale]	2.53	4.21	1.60	5.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model (n=57). When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.68
	Confidence Interval	(2-Sided) 95%; -2.66 to -0.706
	Parameter Dispersion	Type: Standard Deviation; Value: 1.24
	Estimation Comments	Residual standard deviation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 2, Placebo - Period 2
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model (n=57). When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.68
	Confidence Interval	() 95%; -3.85 to -0.139
	Parameter Dispersion	Type: Standard Deviation; Value: 1.24
	Estimation Comments	Residual standard deviation.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

48 partipants who experienced pain in either period 1 or period 2 were included in analysis. All treatment group means are extracted from the mixed effects model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Participants experiencing pain on mexiletine capsules 200 mg orally three times daily in period 1 or period 2	Participants experiencing pain on placebo capsules orally three times dailyin period 1 or period 2
Measure Participants	48	48
Mean (95% Confidence Interval) [units on a scale]	1.54	3.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95%; -2.00 to -1.26
	Parameter Dispersion	Type: Standard Deviation; Value: 1.19
	Estimation Comments	Residual standard deviation.

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

44 partipants who experienced weakness in either period 1 or period 2 were included in analysis. All treatment group means are extracted from the mixed effects model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Particiapnts who experienced weakness on mexiletine capsules 200 mg orally three times daily in either period 1 or period 2.	Particiapnts who experienced weakness on placebo capsules orally three times daily in either period 1 or period 2.
Measure Participants	44	44
Mean (95% Confidence Interval) [units on a scale]	1.96	3.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.26
	Confidence Interval	(2-Sided) 95%; -1.67 to -0.861
	Parameter Dispersion	Type: Standard Deviation; Value: 1.27
	Estimation Comments	Residual standard deviation.

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

49 partipants who experienced tiredness in either period 1 or period 2 were included in analysis. All treatment group means are extracted from the mixed effects model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Particiapnts who experienced tiredness on mexiletine 200 mg capsules orally three times daily in either period 1 or period 2.	Particiapnts who experienced tiredness on placebo capsules orally three times daily in either period 1 or period 2.
Measure Participants	49	49
Mean (95% Confidence Interval) [units on a scale]	2.90	3.82

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.918
	Confidence Interval	(2-Sided) 95%; -1.30 to -0.532
	Parameter Dispersion	Type: Standard Deviation; Value: 1.29
	Estimation Comments	Residual standard deviation.

5. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with quantitative handgrip myotonia values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is a geometric-like mean using log (t+0.1) 'normalizing' transformation. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Average 90% to 5% hand grip relaxation time for particpants receiving mexiletine 200 mg capsules orally three times daily either in period 1 or period 2	Average 90% to 5% hand grip relaxation time for particpants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	54	54
Mean (95% Confidence Interval) [seconds]	0.321	0.429

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.109
	Confidence Interval	(2-Sided) 95%; -0.177 to -0.056
	Parameter Dispersion	Type: Standard Deviation; Value: 0.563
	Estimation Comments	Residual standard deviation.

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with short exercise test values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is taken from the mixed model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Post exercise CMAP amplitude (as a percent of baseline measurement) for particpants receiving mexiletine capsules 200 mg orally three times daily either in period 1 or period 2	Post exercise CMAP amplitude (as a percento f baseline measurement) for particpants receiving mexiletine capsules orally three times daily either in period 1 or period 2
Measure Participants	56	56
Mean (95% Confidence Interval) [percentage of baseline CMAP amplitude]	83.1	78.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.54
	Confidence Interval	(2-Sided) 95%; -0.680 to 9.75
	Parameter Dispersion	Type: Standard Deviation; Value: 13.1
	Estimation Comments	Residual standard deviation.

7. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with graded needle EMG of the RADM values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is taken from the mixed model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Graded myotonia in right ADM for particpants receiving mexiletine capsules 200 mg orally three times daily either in period 1 or period 2	Graded myotonia in right ADM for particpants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	56	56
Mean (95% Confidence Interval) [units on a scale]	2.05	2.62

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wilcoxon test associated with mexiletine effect from the linear mixed effects model. The Wilcoxon test was substituted because the outcome is not continuous and therefore normality of the residuals is not satisfied. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.568
	Confidence Interval	(2-Sided) 95%; -0.812 to -0.325
	Parameter Dispersion	Type: Standard Deviation; Value: 0.600
	Estimation Comments	Residual standard deviation.

8. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with clinical handgrip myotonia values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is a geometric-like mean. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Average time to open the fist after forced hand grip for particpants receiving mexiletine 200 mg capsules orally three times daily either in period 1 or period 2	Average time to open the fist after forced hand grip for particpants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	57	57
Mean (95% Confidence Interval) [Seconds]	0.164	0.494

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.330
	Confidence Interval	(2-Sided) 95%; -0.633 to -0.142
	Parameter Dispersion	Type: Standard Deviation; Value: 1.083
	Estimation Comments	Residual standard deviation.

9. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with clinical eye closure myotonia values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is a geometric-like mean. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Average time to open eyes after forced eye closure for particpants receiving mexiletine 200 mg capsules orally three times daily either in period 1 or period 2	Average time to open eyes after forced eye closure for particpants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	57	57
Mean (95% Confidence Interval) [Seconds]	0.161	0.474

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.313
	Confidence Interval	(2-Sided) 95%; -0.602 to -0.149
	Parameter Dispersion	Type: Standard Deviation; Value: 0.889
	Estimation Comments	Residual standard deviation.

10. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with graded needle EMG of the RTA values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is taken from the mixed model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Graded myotonia in right TA for particpants receiving mexiletine capsules 200 mg orally three times daily either in period 1 or period 2	Graded myotonia in right ADM for particpants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	56	56
Mean (95% Confidence Interval) [units on a scale]	2.07	2.54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wilcoxon test associated with mexiletine effect from the linear mixed effects model. The Wilcoxon test was substituted because the outcome is not continuous and therefore normality of the residuals is not satisfied. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.464
	Confidence Interval	(2-Sided) 95%; -0.675 to -0.254
	Parameter Dispersion	Type: Standard Deviation; Value: 0.516
	Estimation Comments	Residual standard deviation.

11. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with long exercise test values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is taken from the mixed model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	Post exercise CMAP amplitude (as a percentage of baseline measreument) for participants receiving mexiletine capsules 200 mg orally three times daily either in period 1 or period 2	Post exercise CMAP amplitude ( as a percentage of baseline measurement) for participants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	56	56
Mean (95% Confidence Interval) [percentage of baseline CMAP amplitude]	81.8	80.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.69
	Confidence Interval	(2-Sided) 95%; -3.34 to 6.73
	Parameter Dispersion	Type: Standard Deviation; Value: 12.6
	Estimation Comments	Residual standard deviation.

12. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants with INQoL summary score values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is taken from the mixed model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	INQoL summary score for participants receiving mexiletine capsules 200 mg orally three times daily either in period 1 or period 2	INQoL summary score for participants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	51	51
Mean (95% Confidence Interval) [units on a scale]	14.0	16.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.69
	Confidence Interval	(2-Sided) 95%; -4.07 to -1.30
	Parameter Dispersion	Type: Standard Deviation; Value: 3.44
	Estimation Comments	Residual standard deviation.

13. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All participants with SF-36 physical composite values in either period 1 or period 2 were included in analysis. The treatment-specific group mean is taken from the mixed model. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine	Placebo
Arm/Group Description	SF-36 physical composite score for participants receiving mexiletine capsules 200 mg orally three times daily either in period 1 or period 2	SF-36 physical composite score for participants receiving placebo capsules orally three times daily either in period 1 or period 2
Measure Participants	57	57
Mean (95% Confidence Interval) [units on a scale]	44.8	39.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.58
	Confidence Interval	(2-Sided) 95%; 3.44 to 7.72
	Parameter Dispersion	Type: Standard Deviation; Value: 5.35
	Estimation Comments	Residual standard deviation.

14. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Modified intention to treat analysis (n=57). 2 subjects were excluded from analysis due to failure call the IVR system in either period. Treatment group estimates by period are taken from the mixed model, the number above reflecting the number who contributed to the model point estimate. Confidence intervals are bootstrap confidence intervals.

Arm/Group Title	Mexiletine - Period 1	Placebo - Period 1	Mexiletine - Period 2	Placebo - Period 2
Arm/Group Description	SF-36 mental composite for participants receiving mexiletine capsules 200 mg orally three times daily in period 1. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.	SF-36 mental composite for participants receiving placebo capsules orally three times daily in period 1. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.	SF-36 mental composite for participants receiving mexiletine capsules 200 mg orally three times daily in period 2. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.	SF-36 mental composite for participants receiving placebo capsules orally three times daily in period 2. Due to an interaction between period and treatment the primary outcome was presented separately for periods 1 and 2.
Measure Participants	28	29	29	25
Mean (95% Confidence Interval) [units on a scale]	47.4	47.7	53.1	42.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 1, Placebo - Period 1
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.90
	Comments
	Method	Wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.351
	Confidence Interval	(2-Sided) 95%; -5.87 to 5.17
	Parameter Dispersion	Type: Standard Deviation; Value: 6.50
	Estimation Comments	Residual standard deviation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Mexiletine - Period 2, Placebo - Period 2
	Comments	P value indicates significance level of the Wald test associated with mexiletine effect from the linear mixed effects model. When a carryover effect was detected, the significance level associated with the additive portion of the mexiletine effect (labeled period 1) is followed by the level associated with the interaction of mexiletine and period 2 (labeled period 2). All P values were 2-sided and .05 was considered the threshold of statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	wald
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.4
	Confidence Interval	(2-Sided) 95%; 0.941 to 20.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.50
	Estimation Comments	Residual standard deviation.

Adverse Events

Time Frame	Data was collected over a 3 year period
Arm/Group Title	Mexiletine Treatment		Placebo Treatment
Arm/Group Description	Adverse events that occurred when patients were taking placebo.		Adverse events that occurred when patients were taking mexiletine.
All Cause Mortality
	Mexiletine Treatment		Placebo Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mexiletine Treatment		Placebo Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/57 (1.8%)		0/57 (0%)
Psychiatric disorders
Drug withdrawal	1/1 (100%)	1	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Mexiletine Treatment		Placebo Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/57 (42.1%)		11/57 (19.3%)
Blood and lymphatic system disorders
Lymphatics	0/57 (0%)	0	1/57 (1.8%)	1
Cardiac disorders
Cardiac	1/57 (1.8%)	1	1/57 (1.8%)	1
Gastrointestinal disorders
Gastrointestinal	9/57 (15.8%)	9	1/57 (1.8%)	1
General disorders
Constitutional	3/57 (5.3%)	3	0/57 (0%)	0
Pain	4/57 (7%)	4	0/57 (0%)	0
Infections and infestations
Infection	1/57 (1.8%)	1	3/57 (5.3%)	3
Musculoskeletal and connective tissue disorders
Musculosketetal/soft tissue	0/57 (0%)	0	2/57 (3.5%)	2
Nervous system disorders
Neurologic	5/57 (8.8%)	5	1/57 (1.8%)	1
Skin and subcutaneous tissue disorders
Dermatologic/skin	1/57 (1.8%)	1	2/57 (3.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.