Mexiletine in Sporadic Amyotrophic Lateral Sclerosis

Inclusion Criteria

• Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
• Age 18 years or older.
• Symptom onset of weakness or spasticity due to ALS ≤ 60 months prior to Screening Visit.
• Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the screening visit.
• Must be able to swallow capsules throughout the course of the study, according to Site Investigator judgment.
• Capable of providing informed consent and following trial procedures.
• For TMS: a resting motor threshold defined as 50% of pulses eliciting a motor evoked potential (MEP) of amplitude ≥ 50 µV.
• For TTNCS: median Compound Muscle Action Potential (CMAP) ≥ 1.5 mV.
• Subjects must not have taken riluzole for at least 30 days or be on a stable dose of riluzole for at least 30 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).
• 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.
• 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.
• 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

• Invasive ventilator dependence, such as tracheostomy.
• Creatinine level greater than 1.5 mg/dL at screening.
• Serum Glutamic-Oxaloacetic (SGOT/AST) / Serum Glutamic-Pyruvic (SGPT/ALT) 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 30 days prior to Screening Visit.
• 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.
• Metal in the head and neck region, cardiac pacemaker or brain stimulator, cochlear implants, implanted infusion device or personal history of epilepsy.
• Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
• Pregnant women or women currently breastfeeding.
• Placement of Diaphragm Pacing System (DPS) device < 60 days prior to Screening Visit.
• Planned DPS device implantation during study participation