A Safety and Tolerability Study of Mexiletine in Patients with Sporadic ALS (SALS)
Study Purpose:The purpose of this study is to determine if mexiletine is safe and tolerable in volunteers with sporadic ALS (SALS).
Disease:Amyotrophic Lateral Sclerosis (ALS), Sporadic ALS
Study Type:Interventional Trial
Study Category:Drug Trial
Study Status:Not enrolling
Study Chair(s)/Principal Investigator(s):Michael Weiss, MD (University of Washington School of Medicine, Seattle, WA)
Merit Cudkowicz, MD, MSc (Massachusetts General Hospital)
Clinicaltrials.gov ID (11 digit #):NCT01849770
Coordinating Center Contact InformationMass General
Boston, Massachusetts 02109 United States
Full Study Summary: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 to be protective of neurons following spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Recent unpublished studies have shown that mexiletine prolongs survival in animal models of ALS. Since mexiletine has not been rigorously evaluated in ALS populations, a clinical trial has been designed to scientifically determine the safety and tolerability, as well as the effect of mexiletine on ALS patients.
Approximately 60 eligible subjects with sporadic ALS will be recruited from multiple centers in the US. Subjects will be treated for 12 weeks with either mexiletine (300 mg/day or 900 mg/day) or placebo. A follow-up telephone call will occur approximately 4 weeks after completion of the study.
Study Sponsor:ALS Therapy Alliance (ATA) and Northeast ALS (NEALS) Consortium
Participant Duration:Subjects will take study treatment for approximately 12 weeks. Subjects will have 5 in-person visits and 3 telephone calls during the study.
Estimated Study Start Date:06/30/2013
Estimated Study Completion Date:07/31/2014
Posting Last Modified Date:06/30/2015
Date Study Added to alsconsortium.org:05/22/2013
July 1, 2015: ALS ACT will be funding further research
Time since Symptom Onset:<36 months
Time since Diagnosis:N/A
Can participants use Riluzole?Yes
Study subjects meeting all of the following criteria will be allowed to enroll in the study:
1. Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria.
2. Age 18 years or older.
3. Disease duration ≤ 36 months from ALS symptom onset.
4. Capable of providing informed consent and following trial procedures.
5. Subjects must not have taken riluzole for at least 30 days or be on a 50 mg BID dose of riluzole for at least 60 days prior to randomization (riluzole-naÃ¯ve subjects are permitted in the study).
6. Subjects must not have taken medication for muscle cramping such as cyclobenzaprine, baclofen, carisoprodol, or methacarbamol, for at least 30 days prior to randomization or be on a stable dose for at least 60 days prior to randomization.
7. Geographic accessibility to the site.
8. 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.
9. Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the screening visit.
10. Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (i.e., no bleeding disorder, allergy to local anesthetics, a skin infection at or near the LP site, or evidence of high intracranial pressure)
11. Must be able to swallow capsules throughout the course of the study, according to PI judgment.
12. Must have a caregiver assist with dispensing the study drug.
Study subjects meeting any of the following criteria during screening evaluations will be excluded from entry into the study:
1. Invasive ventilator dependence, such as tracheostomy.
2. Creatinine level greater than 1.5 mg/dL.
3. SGOT (AST) / 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 Baseline Visit.
10. Exposure to any other experimental agent (off-label use or investigational) within 30 days prior to Baseline Visit.
11. Use of amiodarone, flecainide, duloxetine, tizanidine, or clozpine.
12. Pregnant women or women currently breastfeeding.
13. Placement of Diaphragm Pacing System (DPS) devise <60 days prior to Baseline Visit.
14. Planned DPS device implantation after Baseline Visit.
Site Contact Information
UCLA, Neuromuscular Research Center
Los Angeles, California 90095
SUNY Upstate Medical Center
Syracuse, New York 13210
University of Washington Medical Center
Seattle, Washington 98195
A phase II, 60 patient NEALS-sponsored multicenter randomized controlled trial of mexiletine in the treatment of ALS was completed. Patients were randomized to placebo, 300 mg, or 900 mg of Mexiletine and followed over 12 weeks. The primary outcome measures were safety and tolerability.
Exploratory measures included effects on the rate of decline of the revised ALS functional rating scale (ALSFRS-R) and slow vital capacity as well as on muscle cramp frequency and severity.
There were no safety issues with Mexiletine at either dose. Some patients had difficulty tolerating the higher dose, largely due to gastrointestinal issues such as nausea, and a few had to stop the drug or reduce the dose. The drug significantly reduced muscle cramp frequency and pain at both doses. With the cramps, if they tolerated it, patients did better at the higher dose than the lower dose. This early phase trial was not powered for efficacy; nor of substantial duration.
Dr. Weiss commented, "The trial clearly shows that Mexiletine is safe to use in ALS patients and reasonably well tolerated, which is what we had hoped when we initiated the study. The dramatic effects on muscle cramps are much more than what we expected and suggest that Mexiletine could become a treatment of choice for this often substantial and debilitating complication of ALS. Determining whether mexiletine can definitively slow progression of the disease will likely require a larger and longer study."
For more details on the preliminary results of this trial, watch this webinar: https://vimeo.com/112947127
Or visit clinicaltrials.gov: https://clinicalt...=20&sel_rss=mod14