| ID | Type | Description | Link |
|---|---|---|---|
| FDA OPD RO1FD003454 |
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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.
Funded by FDAOPD RO1 0003454.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | Participants will receive mexiletine for 4 weeks, then no intervention for 1 week, and finally placebo for 4 weeks. |
|
| 2 | Experimental | Participants will receive placebo for 4 weeks, then no intervention for 1 week, and finally mexiletine for 4 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Mexiletine | Drug | 200 mg three times a day; in pill form |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Patient Reported Weakness on the IVR |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Kansas Medical Center | Kansas City | Kansas | 66160 | United States | ||
| Brigham & Women's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23032552 | Derived | 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. |
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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).
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Mexiletine Then Placebo | 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 |
| FG001 | Placebo Then Mexiletine | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | All participants received all inerventions; therefore, we combined all participants into one Arm/Group. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | Weeks 3-4 of each period |
|
Data was collected over a 3 year period
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Mexiletine Treatment | Adverse events that occurred when patients were taking placebo. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Drug withdrawal | Psychiatric disorders | CTCAE (3.0) | Systematic Assessment | Admitted for withdrawal of narcotics due to pregnancy |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constitutional | General disorders | CTCAE (3.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Richard J. Barohn, MD | University of Kansas Medical Center | 913-588-6095 | rbarohn@kumc.edu |
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| ID | Term |
|---|---|
| D009222 | Myotonia |
| ID | Term |
|---|---|
| D020879 | Neuromuscular Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| D008801 | Mexiletine |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D010647 | Phenyl Ethers |
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| Placebo |
| Drug |
Placebo three times a day; in pill form |
|
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 |
| 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 |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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. |
| 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) |
| Boston |
| Massachusetts |
| 02115 |
| United States |
| University of Rochester School of Medicine & Dentistry | Rochester | New York | 14642 | United States |
| University of Texas Southwestern Medical Center | Dallas | Texas | 75390 | United States |
| London Health Sciences Center | London | Ontario | N6A 5A5 | Canada |
| University of Milan | Milan | Italy |
| Institute of Neurology and National Hospital for Neurology | London | WC1N 3BG | United Kingdom |
| No calls to IVR in either period |
|
| No calls to IVR in period 2 |
|
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo - Period 1 | 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. |
| OG002 | Mexiletine - Period 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. |
| OG003 | Placebo - Period 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. |
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | Weeeks 3-4 of each period |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | Weeks 3-4 of each period |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | Weeks 3-4 of each period |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | seconds | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | percentage of baseline CMAP amplitude | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| Secondary | Clinical Hand Grip Myotonia Evaluation (Seconds) | The time to open the fist after a forced handgrip as measured on a stopwatch. | 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. | Posted | Mean | 95% Confidence Interval | Seconds | The end of period 1 (week 4) and the end of period 2 (week 9) |
|
|
|
|
| Secondary | Clinical Eye Closure Myotonia Evaluation (Seconds) | Time to open the eyes after forced eye closure as measured on a stopwatch. | 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. | Posted | Mean | 95% Confidence Interval | Seconds | The end of period 1 (week 4) and the end of period 2 (week 9) |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| Secondary | Compound Motor Action Potentials After Long Exercise Test | Compound muscle action potential (CMAP) after long periods of exercise as a percentage of baseline. | 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. | Posted | Mean | 95% Confidence Interval | percentage of baseline CMAP amplitude | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | Particiapnts who experienced weakness on mexiletine in either period 1 or period 2. |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | The end of period 1 (week 4) and period 2 (week 9) |
|
|
|
|
| 1 |
| 57 |
| 24 |
| 57 |
| EG001 | Placebo Treatment | Adverse events that occurred when patients were taking mexiletine. | 0 | 57 | 11 | 57 |
|
| Dermatologic/skin | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Systematic Assessment |
|
| Gastrointestinal | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Infection | Infections and infestations | CTCAE (3.0) | Systematic Assessment |
|
| Lymphatics | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Musculosketetal/soft tissue | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | Systematic Assessment |
|
| Neurologic | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Pain | General disorders | CTCAE (3.0) | Systematic Assessment |
|
| Cardiac | Cardiac disorders | CTCAE (3.0) | Systematic Assessment |
|
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D010636 |
| Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| 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. | wald | 0.03 | Mean Difference (Final Values) | 10.4 | Standard Error of the Mean | 6.50 | 2-Sided | 95 | 0.941 | 20.6 | Residual standard deviation. | No | Superiority or Other |