Clinical Efficacy Trial of Mexiletine for Myotonic Dystrophy Type 1

• ClinicalTrials.gov Identifier: NCT01406873
• Recruitment Status: Completed
• First Posted: August 1, 2011
• Results First Posted: March 29, 2018
• Last Update Posted: June 19, 2018
• Sponsor: University of Rochester
• Information provided by (Responsible Party): Chad Heatwole, University of Rochester

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Myotonic Dystrophy	Drug: Mexiletine; Drug: Placebo	Phase 2

Detailed Description:

This study will provide data on the long term (6 months) safety and efficacy of mexiletine in:

• improving the distance participants are able to walk in six minutes;
• reducing myotonia;
• improving muscle strength;
• increasing lean muscle mass;
• decreasing musculoskeletal pain;
• improving gastrointestinal function and swallowing);
• improving functional abilities;
• decreasing cardiac arrhythmias; and
• improving disease-specific health related quality-of-life.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo Controlled, Clinical Efficacy Trial of Mexiletine for Myotonic Dystrophy Type-1 (DM1)
• Study Start Date: June 2011
• Actual Primary Completion Date: February 2017
• Actual Study Completion Date: March 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• A diagnosis of DM1, confirmed by DM1 genetic mutation
• Ability to walk 30 feet (assistance with cane and/or leg bracing permitted)
• Presence of grip myotonia

Exclusion Criteria:

• Congenital DM1
• Treatment with Mexiletine within past 8 weeks
• Second or third degree heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, or is receiving medication for treatment of a cardiac arrhythmia
• Receiving another antimyotonia drug
• Liver or kidney disease requiring ongoing treatment
• Has a seizure disorder
• Is pregnant or lactating
• Had severe depression within 3 months or a history of suicide ideation
• Has any one of the following medical conditions: uncontrolled diabetes mellitus, congestive heart failure, symptomatic cardiomyopathy, symptomatic coronary artery disease, cancer (other than skin cancer) less than five years previously, multiple sclerosis, or other serious medical illness.
• Drug or alcohol abuse within 3 months
• Coexistence of another neuromuscular disease
• Is unable to give informed consent
• Severe arthritis or other medical condition (besides DM1) that would significantly impact ambulation

Contacts and Locations

Locations

United States, New York

University of Rochester Medical Center, Department of Neurology

Rochester, New York, United States, 14642

Sponsors and Collaborators

University of Rochester

Investigators

• Principal Investigator: Richard T. Moxley, III, MD; University of Rochester

  Study Documents (Full-Text)

Documents provided by Chad Heatwole, University of Rochester:

Study Protocol and Statistical Analysis Plan  [PDF] August 22, 2014

More Information

Publications:

Logigian EL, Martens WB, Moxley RT 4th, McDermott MP, Dilek N, Wiegner AW, Pearson AT, Barbieri CA, Annis CL, Thornton CA, Moxley RT 3rd. Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology. 2010 May 4;74(18):1441-8. doi: 10.1212/WNL.0b013e3181dc1a3a.

Moxley RT 3rd, Logigian EL, Martens WB, Annis CL, Pandya S, Moxley RT 4th, Barbieri CA, Dilek N, Wiegner AW, Thornton CA. Computerized hand grip myometry reliably measures myotonia and muscle strength in myotonic dystrophy (DM1). Muscle Nerve. 2007 Sep;36(3):320-8.

• Responsible Party: Chad Heatwole, Associate Professor of Neurology, University of Rochester
• ClinicalTrials.gov Identifier: NCT01406873
• Other Study ID Numbers: 3716; Funding Source: FDA/OOPD ( Other Grant/Funding Number: R01FD003716 )
• First Posted: August 1, 2011
• Results First Posted: March 29, 2018
• Last Update Posted: June 19, 2018
• Last Verified: May 2018

Keywords provided by Chad Heatwole, University of Rochester:

Myotonic Dystrophy; Myotonic Dystrophy Type 1 (DM1); Muscular Dystrophy; Mexiletine

Additional relevant MeSH terms:

Mexiletine; Myotonic Dystrophy; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Myotonic Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action