Effectiveness of Mexiletine for Treating People With Non-Dystrophic Myotonia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Richard Barohn, MD, University of Kansas Medical Center Research Institute
ClinicalTrials.gov Identifier:
NCT00832000
First received: January 27, 2009
Last updated: August 19, 2013
Last verified: August 2013
  Purpose

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 Intervention Phase
Myotonia
Non-Dystrophic Myotonia
Drug: Mexiletine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Therapeutic Trial of Mexiletine in Non-Dystrophic Myotonia

Resource links provided by NLM:


Further study details as provided by University of Kansas:

Primary Outcome Measures:
  • Patient-reported Stiffness on the IVR [ Time Frame: Weeks 3-4 of each period ] [ Designated as safety issue: No ]
    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 [ 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.


Enrollment: 59
Study Start Date: December 2008
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00832000

Locations
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
University of Rochester School of Medicine & Dentistry
Rochester, New York, United States, 14642
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Canada, Ontario
London Health Sciences Center
London, Ontario, Canada, N6A 5A5
Italy
University of Milan
Milan, Italy
United Kingdom
Institute of Neurology and National Hospital for Neurology
London, United Kingdom, WC1N 3BG
Sponsors and Collaborators
Richard Barohn, MD
  More Information

No publications provided by University of Kansas

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Richard Barohn, MD, Gertrude and Dewey Zeigler Professor of Neurology and Chair, University of Kansas Medical Center Research Institute
ClinicalTrials.gov Identifier: NCT00832000     History of Changes
Obsolete Identifiers: NCT00721942
Other Study ID Numbers: 11050, FDA OPD RO1FD003454
Study First Received: January 27, 2009
Results First Received: October 2, 2012
Last Updated: August 19, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Myotonia
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Mexiletine
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014