Clinical trial NCT02781454: Mexiletine in Sporadic Amyotrophic Lateral Sclerosis
Official title: Effect of Mexiletine on Cortical Hyperexcitability in Sporadic Amyotrophic Lateral Sclerosis (SALS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sporadic Amyotrophic Lateral Sclerosis
Keywords: SALS
Mexiletine
TMS
NCS
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Massachusetts General Hospital
First posted: 2016-05-24
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this research study is to find out whether the drug mexiletine will be effective in lowering motor neuron electrical activity in the brains and nerves in the arms of people with ALS. The investigators will also determine if there are any signs that the drug may slow down the progression of ALS and reduce muscle cramps and muscle twitching. This will be determined through transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS). In this trial, the participants will be taking either 300mg/day of mexiletine, 600mg/day of mexiletine, or placebo (non-active study drug).

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 Recent unpublished studies in the laboratory of Dr.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.

Eligibility criteria: Inclusion Criteria:

1. Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
2. Age 18 years or older.
3. Symptom onset of weakness or spasticity due to ALS ≤ 60 months prior to Screening Visit.
4. Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the screening visit.
5. Must be able to swallow capsules throughout the course of the study, according to Site Investigator judgment.
6. Capable of providing informed consent and following trial procedures.
7. For TMS: a resting motor threshold defined as 50% of pulses eliciting a motor evoked potential (MEP) of amplitude ≥ 50 µV.
8. For TTNCS: median Compound Muscle Action Potential (CMAP) ≥ 1.5 mV.
9. 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).
10. 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.
11. Geographic accessibility to the site.
12. 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.
13. 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:

1. Invasive ventilator dependence, such as tracheostomy.
2. Creatinine level greater than 1.5 mg/dL at screening.
3. Serum Glutamic-Oxaloacetic (SGOT/AST) / Serum Glutamic-Pyruvic (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 30 days prior to Screening Visit.
10. 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.
11. Metal in the head and neck region, cardiac pacemaker or brain stimulator, cochlear implants, implanted infusion device or personal history of epilepsy.
12. Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
13. Pregnant women or women currently breastfeeding.
14. Placement of Diaphragm Pacing System (DPS) device \< 60 days prior to Screening Visit.
15. Planned DPS device implantation during study participation

Primary outcomes:
measure: Change in Resting Motor Threshold
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported
Secondary outcomes:
measure: Effect on Short-interval Intracortical Inhibition
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Change in Motor Evoked Potential Amplitude
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Cortical Silent Period
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Strength Duration Time Constant
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Depolarizing Threshold Electrotonus (90-100 ms)
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms)
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Superexcitability
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Subexcitability
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Effect on Frequency of Muscle Cramps
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported
measure: Effect on Frequency of Fasciculations (Muscle Twitching)
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported
Other outcomes:
measure: Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
measure: Change in Slow Vital Capacity
timeFrame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Columbia Universtiy Medical Center
state: New York
city: Hershey
country: United States
facility: Pennsylvania State Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Washington
name: Michael Weiss, MD
role: PRINCIPAL_INVESTIGATOR
References: