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Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (Mexiletine-2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2016 by University of Washington
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
Michael D Weiss, University of Washington
ClinicalTrials.gov Identifier:
NCT02781454
First received: May 10, 2016
Last updated: December 22, 2016
Last verified: December 2016
  Purpose
The purpose of this research study is to find out whether the drug mexiletine will be effective in lowering motor neuron electrical activity in the brains and nerves in the arms of people with ALS. The investigators will also determine if there are any signs that the drug may slow down the progression of ALS and reduce muscle cramps and muscle twitching. This will be determined through transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS). In this trial, the participants will be taking either 300mg/day of mexiletine, 600mg/day of mexiletine, or placebo (non-active study drug).

Condition Intervention Phase
Sporadic Amyotrophic Lateral Sclerosis
Drug: Mexiletine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Mexiletine on Cortical Hyperexcitability in Sporadic Amyotrophic Lateral Sclerosis (SALS)

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • Change in resting motor threshold [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, will be used as the primary pharmacodynamic marker of cortical hyperexcitability.


Secondary Outcome Measures:
  • Effects on motor evoked potential (MEP) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from single pulse transcranial magnetic stimulation (TMS)

  • Effects on strength duration time constant [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from threshold tracking nerve conduction studies (TTNCS)

  • Effect on frequency and severity of muscle cramps [ Time Frame: Baseline, Week 4, and Week 8 ]
    Will be assessed using a daily muscle cramps diary and assessment form at Baseline.

  • Effects on cortical silent period [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from single pulse transcranial magnetic stimulation (TMS)

  • Effects on short-interval intracortical inhibition (SICI) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from dual pulse transcranial magnetic stimulation (TMS)

  • Effects on threshold electrotonus [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from threshold tracking nerve conduction studies (TTNCS)

  • Effect on frequency and severity of fasciculations (muscle twitching) [ Time Frame: Baseline, Week 4, and Week 8 ]
    Will be assessed using a daily fasciculations diary and assessment form at Baseline.


Other Outcome Measures:
  • Evaluate changes in slow vital capacity (SVC) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
  • Evaluate changes in the ALS Functional Rating Scale - revised (ALSFRS-R) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]

Estimated Enrollment: 60
Study Start Date: October 2016
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Mexiletine, 300 milligrams
Mexiletine, 300 milligrams by mouth per day for 4 weeks.
Drug: Mexiletine
Other Name: Mexitil
Active Comparator: Mexiletine, 600 milligrams
Mexiletine, 600 milligrams by mouth per day for 4 weeks.
Drug: Mexiletine
Other Name: Mexitil
Placebo Comparator: Placebo
Placebo, by mouth per day for 4 weeks.
Drug: Placebo

Detailed Description:
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons, for which treatment designed to slow or arrest progression remains lacking. Mexiletine is a use-dependent sodium channel blocker that has been FDA-approved for decades for the treatment of cardiac arrhythmias and more recently to treat neuropathic pain in diabetic polyneuropathy. Mexiletine has been shown also to be protective of neurons following spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Based on previous studies, mexiletine appears to penetrate into the central nervous system at concentrations sufficient to confer significant protection. Recent unpublished studies in the laboratory of Dr. Robert Brown at the University of Massachusetts have also demonstrated that mexiletine ingestion in mice genetically engineered to express high levels of mutant cytosolic copper-zinc superoxide dismutase-1 (SOD1) transgene prolongs survival in these animals. As mexiletine already has FDA-approval as an anti-arrhythmic agent, much is known about the pharmacology and safety of this drug in non-ALS patients. We anticipate that by excluding subjects with a known history of cardiac disease and with the known neuroprotectant properties of this medication, mexiletine is a good choice for further study in an ALS clinical trial.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
  2. Age 18 years or older.
  3. Symptom onset of weakness or spasticity due to ALS ≤ 24 months prior to Screening Visit.
  4. Slow vital capacity (SVC) measure ≥65% of predicted for gender, height, and age at the screening visit.
  5. Must be able to swallow capsules throughout the course of the study, according to Site Investigator judgment.
  6. Capable of providing informed consent and following trial procedures.
  7. For TMS: a resting motor threshold ≤ 83% of stimulator output, with 50% of pulses eliciting a motor evoked potential (MEP) of amplitude ≥ 50 µV.
  8. For TTNCS: median Compound Muscle Action Potential (CMAP) ≥ 1.5 mV.
  9. Subjects must not have taken riluzole for at least 30 days or be on a stable dose of riluzole for at least 60 days prior to the Screening Visit and continue on the stable dose throughout the course of the study (riluzole-naïve subjects are permitted in the study).
  10. Subjects must not have taken medication for muscle cramping such as cyclobenzaprine, baclofen, carisoprodol, or methocarbamol, for at least 30 days prior to screening or be on a stable dose for at least 60 days prior to screening.
  11. Geographic accessibility to the site.
  12. Women must not become pregnant for the duration of the study and must be willing to use two contraceptive therapies and have a negative pregnancy test throughout the course of the study.
  13. Use of medications known to affect the neurophysiology measures in the study must be scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose for 30 days prior to the Screening Visit, and there must be no reason to believe that a subsequent change would be necessary during the course of the study. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamines) and anti-cholinergics.

Exclusion Criteria:

  1. Invasive ventilator dependence, such as tracheostomy.
  2. Creatinine level greater than 1.5 mg/dL at screening.
  3. Serum Glutamic-Oxaloacetic (SGOT/AST) / Serum Glutamic-Pyruvic (SGPT/ALT) greater than 3 times the upper limit of normal at screening.
  4. History of known sensitivity or intolerability to mexiletine or lidocaine.
  5. Any history of either substance abuse within the past year, unstable psychiatric disease, cognitive impairment, or dementia.
  6. Clinically significant conduction abnormalities on electrocardiogram or a known history of cardiac arrhythmia.
  7. Known history of epilepsy.
  8. Known history of congestive heart failure (CHF) or history of myocardial infarction within the past 24 months.
  9. Use of mexiletine for 60 days prior to Screening Visit.
  10. Exposure to any other experimental agent (off-label use or investigational) including high dose creatine (>10 grams a day) within 30 days prior to Screening Visit.
  11. Metal in the head and neck region, cardiac pacemaker or brain stimulator, cochlear implants, implanted infusion device or personal history of epilepsy.
  12. Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
  13. Pregnant women or women currently breastfeeding.
  14. Placement of Diaphragm Pacing System (DPS) device < 60 days prior to Screening Visit.
  15. Planned DPS device implantation during study participation
  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: NCT02781454

Contacts
Contact: Sara Vaughan, BA 617-643-5374 svaughan2@partners.org

Locations
United States, Arizona
Barrow Neurological Institute Recruiting
Phoenix, Arizona, United States, 85013
Contact: Ashley Reece    602-406-4775    ashley.reece@dignityhealth.org   
United States, California
University of California, Irvine Recruiting
Orange, California, United States, 92868
Contact: Veena Mathew    714-456-2864    vmathew@uci.edu   
United States, Georgia
Augusta University Not yet recruiting
Augusta, Georgia, United States, 30912
Contact: Nicole Smalley    706-721-2681    nsmalley@augusta.edu   
United States, Massachusetts
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Carmen Shin    617-667-3053    cshin1@bidmc.harvard.edu   
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Jayna Duell    734-763-9037    jkballar@med.umich.edu   
United States, New York
Columbia Universtiy Medical Center Not yet recruiting
New York, New York, United States, 10032
Contact: Jess Singleton    212-305-7221    jes2186@cumc.columbia.edu   
United States, Pennsylvania
University of Pittsburgh Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Danielle Rowlands    412-864-2873    doerdx@upmc.edu   
United States, Washington
University of Washington Not yet recruiting
Seattle, Washington, United States, 98195
Contact: Sharon Downing    206-543-0081    sdowning@uw.edu   
Sponsors and Collaborators
University of Washington
Massachusetts General Hospital
Investigators
Principal Investigator: Michael Weiss, MD University of Washington
  More Information

Additional Information:
Responsible Party: Michael D Weiss, Professor, Department of Neurology, University of Washington
ClinicalTrials.gov Identifier: NCT02781454     History of Changes
Other Study ID Numbers: MX-ALS-002
Study First Received: May 10, 2016
Last Updated: December 22, 2016

Keywords provided by University of Washington:
SALS
Mexiletine
TMS
NCS

Additional relevant MeSH terms:
Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Mexiletine
Anti-Arrhythmia Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on March 28, 2017