Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 Recent unpublished studies in the laboratory of Dr.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.

Official Title
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A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)

Conditions
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Sporadic Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Mexiletine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mexiletine, 300 milligrams<br>Mexiletine, 300 milligrams by mouth per day for 12 weeks. | Drug: Mexiletine<br> <br> * Other names: Mexitil;|
| Active Comparator: Mexiletine, 900 milligrams<br>Mexiletine, 900 milligrams by mouth per day for 12 weeks. | Drug: Mexiletine<br> <br> * Other names: Mexitil;|
| Placebo Comparator: Placebo<br>Placebo, by mouth per day for 12 weeks. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Discontinued Study Drug | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Plasma Concentration (Cmin) of Mexiletine | Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit. | Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) | 
| Peak Plasma Concentration (Cmax) of Mexiletine | Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit. | Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) | 
| Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. | Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit. | Week 6 Visit (up to 6 hours post dose) | 
| Mean Cerebrospinal Fluid (CSF)/Plasma Ratio | The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma. | Week 6 Visit (up to 6 hours post dose) | 
| Mean Weekly Cramp Frequency |  | Week 3-12, post titration of study medication | 
| Maximal Pain Severity | 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. | Weeks 3-12, post titration of study medication | 
| Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 |  | Week 3-12, post titration of study medication | 
| Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 |  | Week 3-12, post titration of study medication | 
| Mean Pain Severity | 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. | Weeks 3-12, post titration of study medication | 
| Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 |  | Week 3-12, post titration of study medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SALS, Mexiletine, Safety