Mexiletine in Sporadic Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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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
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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 Recent unpublished studies in the laboratory of Dr.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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Effect of Mexiletine on Cortical Hyperexcitability in 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 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

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 4 weeks. | Drug: Mexiletine<br> <br> * Other names: Mexitil;|
| Active Comparator: Mexiletine, 600 milligrams<br>Mexiletine, 600 milligrams by mouth per day for 4 weeks. | Drug: Mexiletine<br> <br> * Other names: Mexitil;|
| Placebo Comparator: Placebo<br>Placebo, by mouth per day for 4 weeks. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Resting Motor Threshold | The resting motor threshold (RMT) assessed from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, was used as the primary pharmacodynamic marker of cortical hyperexcitability. RMT is the stimulus intensity required to produce and maintain a 0.2 mV peak-to-peak motor evoked potential of the abductor pollicis brevis muscle by TMS. A smaller RMT is thought to suggest greater neuronal excitability. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on Short-interval Intracortical Inhibition | Short-interval intracortical inhibition (SICI) is a measure of neuronal excitability measured by dual pulse TMS with a conditioned (80% of RMT) and test pulses (120% of RMT) to generate a stable MEP amplitude of 0.2 mV, averaged over interstimulus intervals of 1-7 ms. It is thought to reflect refractory cortical axons and subsequent resynchronization of cortico-cortical and corticomotoneuronal volleys or activation of non-GABAergic cortical inhibitory circuits (initial phase) and synaptic neurotransmission through GABAA receptors (second phase). The value for SICI thought to be maximally sensitive for detecting in changes in ALS subjects compared to controls is is derived by measuring the motor evoked potential amplitude (MEP) at an interstimulus interval of 3 ms (ISI 3 ms) and normalizing to the MEP amplitude at 120% of the resting motor threshold (MEP 120% RMT). A reduction in SICI reflecting greater excitability would generate a larger ratio of MEP ISI 3 ms/MEP 120% RMT. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Change in Motor Evoked Potential Amplitude | The motor evoked potential (MEP) amplitude is taken from single pulse transcranial magnetic stimulation (TMS) and reflects the density of corticomotoneuronal projections onto motor neurons and is affected by cortical hyperexcitability early in ALS where it is thought to be larger than age-matched controls and axonal degeneration later in the disease when it decreases in amplitude. The MEP is most reliable in assessing cortical motor neuronal preservation and excitability when normalized to the peak compound nerve action potential (CMAP) amplitude which reflects the integrity of peripheral motor nerve axons. It is also normalized here to 120% of the RMT to derive a ratio of MEP at 120% RMT/peak CMAP. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Cortical Silent Period | The cortical silent period (CSP) is recorded with single pulse TMS as a duration from the onset of the MEP response to resumption of voluntary electromyography activity with the patient performing a voluntary contraction, set to 30% of maximal voluntary contraction. A shorter CSP compared to controls would reflect greater excitability. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Strength Duration Time Constant | The strength duration time constant (SDTC) is used in threshold tracking nerve axonal excitability studies and is interpreted as a measure of axonal excitability that is dependent upon the biophysical properties of the axonal membrane at the node of Ranvier, especially persistent sodium current. It is derived from the relationship between stimulus duration and intensity. A higher SDTC would reflect greater excitability of motor nerve axons. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Depolarizing Threshold Electrotonus (90-100 ms) | Depolarizing threshold electrotonus (90-100 ms) (TEd 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold depolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with a decrease in the membrane excitability threshold due to opening of potassium channels on the axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure, presumably by decreasing TEd 90-100 ms more substantially than normal. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | Hyperpolarizing threshold electrotonus (90-100 ms) (TEh 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold hyperpolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with an increase in the membrane excitability threshold due to closure of potassium channels causing increased resistance of the internodal axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Superexcitability | Superexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a depolarizing afterpotential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and reflects passive depolarization of the internodal axon. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Subexcitability | Subexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a late hyperpolarizing after potential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and is related to the very slow turn-off of slow potassium channels. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 
| Effect on Frequency of Muscle Cramps | Will be assessed using a daily muscle cramps diary tabulated weekly beginning at Baseline. | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported | 
| Effect on Frequency of Fasciculations (Muscle Twitching) | Will be assessed using a daily fasciculations diary tabulated as a percentage of days from weeks 3-4. | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported | 

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