Overview

This trial is active, not recruiting.

Condition sporadic amyotrophic lateral sclerosis
Treatments mexiletine, placebo
Phase phase 2
Sponsor University of Washington
Start date July 2013
End date August 2014
Trial size 60 participants
Trial identifier NCT01849770, 2012P001875

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose treatment
Arm
(Active Comparator)
Mexiletine, 300 milligrams by mouth per day for 12 weeks.
mexiletine Mexitil
(Active Comparator)
Mexiletine, 900 milligrams by mouth per day for 12 weeks.
mexiletine Mexitil
(Placebo Comparator)
Placebo, by mouth per day for 12 weeks.
placebo

Primary Outcomes

Measure
Change in the safety and tolerability of mexiletine at 2 doses (300 milligrams mexiletine and 900 milligrams mexiletine) as assessed by the number of adverse events experienced over time.
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.

Secondary Outcomes

Measure
Trough serum concentration (Cmin) of mexiletine
time frame: Week 6 Visit (up to 6 hours post dose)
Time to peak concentration of mexiletine in cerebral spinal fluid
time frame: Week 6 Visit (up to 6 hours post dose)
Peak serum concentration (Cmax) of mexiletine
time frame: Week 6 Visit (up to 6 hours post dose)
Time to peak concentration of mexiletine in serum
time frame: Week 6 Visit (up to 6 hours post dose)
Elimination half-life of mexiletine in serum
time frame: Week 6 Visit (up to 6 hours post dose)
Area under the concentration time curve (AUC) of mexiletine in serum.
time frame: Week 6 Visit (up to 6 hours post dose)
Trough cerebral spinal fluid concentration (Cmin) of mexiletine
time frame: Week 6 Visit (up to 6 hours post dose)
Peak cerebral spinal fluid concentration (Cmax) of mexiletine
time frame: Week 6 Visit (up to 6 hours post dose)
Elimination half-life of mexiletine in cerebral spinal fluid
time frame: Week 6 Visit (up to 6 hours post dose)
Area under the concentration time curve (AUC)of mexiletine in cerebral spinal fluid
time frame: Week 6 Visit (up to 6 hours post dose)

Eligibility Criteria

Male or female participants at least 18 years old.

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.

Additional Information

Official title A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)
Principal investigator Michael D Weiss, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in July 2014.
Information provided to ClinicalTrials.gov by University of Washington.