Sporadic Amyotrophic Lateral Sclerosis
Conditions
Keywords
SALS, Mexiletine, TMS, NCS
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 Recent unpublished studies in the laboratory of Dr.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.
Interventions
DRUGMexiletine
DRUGPlacebo
Sponsors
Massachusetts General Hospital
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Resting Motor Threshold | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect on Short-interval Intracortical Inhibition | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Change in Motor Evoked Potential Amplitude | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Effect on Cortical Silent Period | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Effect on Strength Duration Time Constant | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Effect on Depolarizing Threshold Electrotonus (90-100 ms) | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Effect on Frequency of Muscle Cramps | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported | Will be assessed using a daily muscle cramps diary tabulated weekly beginning at Baseline. |
| Effect on Frequency of Fasciculations (Muscle Twitching) | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported | Will be assessed using a daily fasciculations diary tabulated as a percentage of days from weeks 3-4. |
| Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Effect on Superexcitability | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
| Effect on Subexcitability | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) is an instrument for evaluating the functional status of patients with ALS that includes functions related to speech, swallowing, salivation, fine motor control, gross motor function, and respiration. The score is the sum of 12 items (range 0 to 48) with higher scores reflecting better function. |
| Change in Slow Vital Capacity | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported | Measure of decline in respiratory muscle strength |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled at 9 Northeast ALS Consortium (NEALS) centers in the US. These NEALS centers were academic clinical research centers with established practices where sporadic ALS (sALS) patients are regularly seen and treated.
Pre-assignment details
Within 21 days prior to treatment assignment, patients were screened for eligibility based on inclusion/exclusion criteria. Failure to meet any of these criteria at the time of this screening would result in exclusion from the study, and these patients would not be assigned to a treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Mexiletine, 300 Milligrams Mexiletine, 300 milligrams by mouth per day for 4 weeks.
Mexiletine | 8 |
| Mexiletine, 600 Milligrams Mexiletine, 600 milligrams by mouth per day for 4 weeks.
Mexiletine | 6 |
| Placebo Placebo, by mouth per day for 4 weeks.
Placebo | 6 |
| Total | 20 |
Baseline characteristics
| Characteristic | Mexiletine, 600 Milligrams | Total | Mexiletine, 300 Milligrams | Placebo |
|---|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 14.1 | 57.2 years STANDARD_DEVIATION 11.9 | 58.5 years STANDARD_DEVIATION 10.8 | 52.0 years STANDARD_DEVIATION 11.3 |
| El Escorial Diagnosis Definite | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| El Escorial Diagnosis Possible | 0 Participants | 4 Participants | 1 Participants | 3 Participants |
| El Escorial Diagnosis Probable | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| El Escorial Diagnosis Prob Lab Supported | 5 Participants | 12 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 19 Participants | 8 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 20 Participants | 8 Participants | 6 Participants |
| Region of Enrollment United States | 6 Participants | 20 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 14 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 5 / 8 | 5 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 1 / 6 |
Outcome results
Primary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Mexiletine, 300 Milligrams | Change in Resting Motor Threshold | change from baseline to week 4 | -2.430 percentage of maximum stimulus output | Standard Error 2.323 |
| Mexiletine, 300 Milligrams | Change in Resting Motor Threshold | change from week 4 to week 8 | 1.465 percentage of maximum stimulus output | Standard Error 2.357 |
| Mexiletine, 600 Milligrams | Change in Resting Motor Threshold | change from baseline to week 4 | 0.805 percentage of maximum stimulus output | Standard Error 2.207 |
| Mexiletine, 600 Milligrams | Change in Resting Motor Threshold | change from week 4 to week 8 | -0.284 percentage of maximum stimulus output | Standard Error 2.169 |
| Placebo | Change in Resting Motor Threshold | change from week 4 to week 8 | -2.908 percentage of maximum stimulus output | Standard Error 2.247 |
| Placebo | Change in Resting Motor Threshold | change from baseline to week 4 | 4.746 percentage of maximum stimulus output | Standard Error 2.185 |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.03995% CI: [-10.8, -0.315]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
Population: MEP at 120% RMT/peak CMAP
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Change in Motor Evoked Potential Amplitude | 0.589 unitless ratio of ms/ms |
| Mexiletine, 600 Milligrams | Change in Motor Evoked Potential Amplitude | 0.490 unitless ratio of ms/ms |
| Placebo | Change in Motor Evoked Potential Amplitude | 1.308 unitless ratio of ms/ms |
Comparison: Comparison of active (300 and 600 mg) vs placebo ratio of week 4 to week 0p-value: 0.01395% CI: [0.208, 0.81]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Cortical Silent Period | 3.937 milliseconds |
| Mexiletine, 600 Milligrams | Effect on Cortical Silent Period | 4.823 milliseconds |
| Placebo | Effect on Cortical Silent Period | 4.037 milliseconds |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.98695% CI: [-41.36, 42.042]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Depolarizing Threshold Electrotonus (90-100 ms) | -0.140 percentage of threshold depolarization |
| Mexiletine, 600 Milligrams | Effect on Depolarizing Threshold Electrotonus (90-100 ms) | 4.005 percentage of threshold depolarization |
| Placebo | Effect on Depolarizing Threshold Electrotonus (90-100 ms) | 0.844 percentage of threshold depolarization |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.69495% CI: [-4.609, 6.786]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Frequency of Fasciculations (Muscle Twitching) | 100 percentage of days with fasciculations |
| Mexiletine, 600 Milligrams | Effect on Frequency of Fasciculations (Muscle Twitching) | 100 percentage of days with fasciculations |
| Placebo | Effect on Frequency of Fasciculations (Muscle Twitching) | 100 percentage of days with fasciculations |
Secondary
Effect on Frequency of Muscle Cramps
Will be assessed using a daily muscle cramps diary tabulated weekly beginning at Baseline.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Frequency of Muscle Cramps | 3.430 muscle cramps/week |
| Mexiletine, 600 Milligrams | Effect on Frequency of Muscle Cramps | 1.987 muscle cramps/week |
| Placebo | Effect on Frequency of Muscle Cramps | 3.774 muscle cramps/week |
Comparison: Comparison of active (300 and 600 mg) vs placebop-value: 0.71395% CI: [0.111, 4.535]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | -10.184 percentage threshold hyperpolarization |
| Mexiletine, 600 Milligrams | Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | 2.230 percentage threshold hyperpolarization |
| Placebo | Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | -4.219 percentage threshold hyperpolarization |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.96995% CI: [-12.64, 13.126]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Short-interval Intracortical Inhibition | 0.655 unitless ratio MEP ISI 3 ms/MEP 120% RMT |
| Mexiletine, 600 Milligrams | Effect on Short-interval Intracortical Inhibition | 0.886 unitless ratio MEP ISI 3 ms/MEP 120% RMT |
| Placebo | Effect on Short-interval Intracortical Inhibition | 0.961 unitless ratio MEP ISI 3 ms/MEP 120% RMT |
Comparison: Comparison of active (300 and 600 mg) vs placebo ratio of week 4 to week 0p-value: 0.33295% CI: [0.484, 1.296]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
Population: strength duration time constant
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Strength Duration Time Constant | 0.895 milliseconds |
| Mexiletine, 600 Milligrams | Effect on Strength Duration Time Constant | 0.966 milliseconds |
| Placebo | Effect on Strength Duration Time Constant | 0.935 milliseconds |
Comparison: Comparison of active (300 and 600 mg) vs placebo ratio of week 4 to week 0p-value: 0.91595% CI: [0.876, 1.126]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Subexcitability | -2.563 percentage of threshold change |
| Mexiletine, 600 Milligrams | Effect on Subexcitability | -0.575 percentage of threshold change |
| Placebo | Effect on Subexcitability | 0.448 percentage of threshold change |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.27395% CI: [-5.767, 1.733]Mixed Models Analysis
Secondary
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.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Effect on Superexcitability | 2.234 percentage of threshold change |
| Mexiletine, 600 Milligrams | Effect on Superexcitability | 1.511 percentage of threshold change |
| Placebo | Effect on Superexcitability | -0.724 percentage of threshold change |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.32395% CI: [-2.772, 7.966]Mixed Models Analysis
Other Pre-specified
Change in Slow Vital Capacity
Measure of decline in respiratory muscle strength
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Change in Slow Vital Capacity | -0.532 maximum percent predicted |
| Mexiletine, 600 Milligrams | Change in Slow Vital Capacity | -6.918 maximum percent predicted |
| Placebo | Change in Slow Vital Capacity | -0.991 maximum percent predicted |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.28595% CI: [-7.938, 2.471]Mixed Models Analysis
Other Pre-specified
Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) is an instrument for evaluating the functional status of patients with ALS that includes functions related to speech, swallowing, salivation, fine motor control, gross motor function, and respiration. The score is the sum of 12 items (range 0 to 48) with higher scores reflecting better function.
Time frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mexiletine, 300 Milligrams | Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised | -1.414 score on a scale |
| Mexiletine, 600 Milligrams | Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised | -1.038 score on a scale |
| Placebo | Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised | -0.827 score on a scale |
Comparison: Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4p-value: 0.60195% CI: [-1.966, 1.169]Mixed Models Analysis