Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS) (MX-ALS-001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01849770
Recruitment Status : Completed
First Posted : May 8, 2013
Results First Posted : October 12, 2015
Last Update Posted : October 12, 2015
Sponsor:
Information provided by (Responsible Party):
Michael D Weiss, University of Washington

Brief Summary:
The purpose of this research is to find out if mexiletine is safe and effective in people with Amyotrophic Lateral Sclerosis (ALS). In this trial, participants will be taking either 300 milligrams per day of mexiletine, 900 milligrams per day of mexiletine or placebo (non-active study drug). The safety and efficacy of these doses will be compared to see if one dose is better than the other.

Condition or disease Intervention/treatment Phase
Sporadic Amyotrophic Lateral Sclerosis Drug: Mexiletine Drug: Placebo Phase 2

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 Recent unpublished studies in the laboratory of Dr.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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)
Study Start Date : July 2013
Actual Primary Completion Date : August 2014
Actual Study Completion Date : August 2014


Arm Intervention/treatment
Active Comparator: Mexiletine, 300 milligrams
Mexiletine, 300 milligrams by mouth per day for 12 weeks.
Drug: Mexiletine
Other Name: Mexitil

Active Comparator: Mexiletine, 900 milligrams
Mexiletine, 900 milligrams by mouth per day for 12 weeks.
Drug: Mexiletine
Other Name: Mexitil

Placebo Comparator: Placebo
Placebo, by mouth per day for 12 weeks.
Drug: Placebo



Primary Outcome Measures :
  1. Percentage of Participants That Discontinued Study Drug [ Time Frame: Screening, Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Adverse Events will be assessed via telephone Weeks 1, 10, and 16. ]
    Information on adverse effects of mexiletine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results.


Secondary Outcome Measures :
  1. Trough Plasma Concentration (Cmin) of Mexiletine [ Time Frame: Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) ]
    Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.

  2. Peak Plasma Concentration (Cmax) of Mexiletine [ Time Frame: Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) ]
    Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.

  3. Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. [ Time Frame: Week 6 Visit (up to 6 hours post dose) ]
    Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.

  4. Mean Cerebrospinal Fluid (CSF)/Plasma Ratio [ Time Frame: Week 6 Visit (up to 6 hours post dose) ]
    The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma.

  5. Mean Weekly Cramp Frequency [ Time Frame: Week 3-12, post titration of study medication ]
  6. Maximal Pain Severity [ Time Frame: Weeks 3-12, post titration of study medication ]

    At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days.

    The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms.

    Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily.


  7. Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 [ Time Frame: Week 3-12, post titration of study medication ]
  8. Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 [ Time Frame: Week 3-12, post titration of study medication ]
  9. Mean Pain Severity [ Time Frame: Weeks 3-12, post titration of study medication ]

    At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days.

    The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms.

    Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily.


  10. Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 [ Time Frame: Week 3-12, post titration of study medication ]

Other Outcome Measures:
  1. Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score [ Time Frame: Week 0, Week 2, Week 6, Week 12 (or Early Termination Date), and Week 16 ]
    The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival.

  2. Change in Slow Vital Capacity (SVC) Score [ Time Frame: Week 0, Week 6, and Week 12 (or Early Termination Date) ]
    The vital capacity (VC) (percent of predicted normal) will be determined, using the slow VC method. The SVC can be measured using conventional spirometers that have had a calibration check prior to subject testing. A printout from the spirometer of all SVC trials will be retained.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Sporadic Amyotrophic Lateral Sclerosis (SALS) diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
  • Age 18 years or older.
  • Disease duration ≤ 36 months from ALS symptom onset.
  • Capable of providing informed consent and following trial procedures.
  • Subjects must not have taken riluzole for at least 30 days or be on a 50 milligrams twice daily dose of riluzole for at least 60 days prior to randomization (riluzole-naïve subjects are permitted in the study).
  • Subjects must not have taken medication for muscle cramping such as cyclobenzaprine, baclofen, carisoprodol, or methocarbamol, for at least 30 days prior to randomization or be on a stable dose for at least 60 days prior to randomization.
  • Geographic accessibility to the site.
  • 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.
  • Slow vital capacity (SVC) measure greater than or equal to 50% of predicted for gender, height, and age at the screening visit.
  • Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (for example, no bleeding disorder, allergy to local anesthetics, a skin infection at or near the LP site, or evidence of high intracranial pressure).
  • Must be able to swallow capsules throughout the course of the study, according to Principal Investigator (PI) judgment.
  • Must have a caregiver assist with dispensing the study drug.

Exclusion Criteria:

  • Invasive ventilator dependence, such as tracheostomy.
  • Creatinine level greater than 1.5 milligram/deciliter.
  • Serum glutamic oxaloacetic transaminase or (aspartate transaminase) / serum glutamic pyruvic transaminase (alanine aminotransferase) greater than 3 times the upper limit of normal at screening.
  • History of known sensitivity or intolerability to mexiletine or lidocaine.
  • Any history of either substance abuse within the past year, unstable psychiatric disease, cognitive impairment, or dementia.
  • Clinically significant conduction abnormalities on electrocardiogram or a known history of cardiac arrhythmia.
  • Known history of epilepsy.
  • Known history of congestive heart failure (CHF) or history of myocardial infarction within the past 24 months.
  • Use of mexiletine for 60 days prior to Baseline Visit.
  • Exposure to any other experimental agent (off-label use or investigational) including high dose creatine (greater than 10 grams a day) within 30 days prior to Baseline Visit.
  • Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
  • Pregnant women or women currently breastfeeding.
  • Placement of Diaphragm Pacing System (DPS) device less than 60 days prior to Baseline Visit.
  • Planned DPS device implantation after Baseline Visit.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01849770


Locations
Layout table for location information
United States, California
UCLA, Neuromuscular Research Center
Los Angeles, California, United States, 90095
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
University of Massachusetts (Worcester) Memorial Medical Center
Worcester, Massachusetts, United States, 01655
United States, Missouri
Washington University Medical School
Saint Louis, Missouri, United States, 63110
United States, New York
SUNY Upstate Medical Center
Syracuse, New York, United States, 13210
United States, Pennsylvania
Penn State Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75390-8897
United States, Washington
University of Washington Medical Center
Seattle, Washington, United States, 98195
Sponsors and Collaborators
University of Washington
Investigators
Layout table for investigator information
Principal Investigator: Michael D Weiss, MD University of Washington Medical School

Additional Information:
Layout table for additonal information
Responsible Party: Michael D Weiss, Associate Professor, Department of Neurology, University of Washington
ClinicalTrials.gov Identifier: NCT01849770     History of Changes
Other Study ID Numbers: 43708-A
First Posted: May 8, 2013    Key Record Dates
Results First Posted: October 12, 2015
Last Update Posted: October 12, 2015
Last Verified: September 2015

Keywords provided by Michael D Weiss, University of Washington:
SALS
Mexiletine
Safety

Additional relevant MeSH terms:
Layout table for 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