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Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (Mexiletine-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02781454
Recruitment Status : Completed
First Posted : May 24, 2016
Results First Posted : December 5, 2019
Last Update Posted : December 5, 2019
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
Michael D Weiss, University of Washington

Tracking Information
First Submitted Date  ICMJE May 10, 2016
First Posted Date  ICMJE May 24, 2016
Results First Submitted Date  ICMJE October 6, 2019
Results First Posted Date  ICMJE December 5, 2019
Last Update Posted Date December 5, 2019
Actual Study Start Date  ICMJE October 2016
Actual Primary Completion Date September 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 17, 2019)
Change in Resting Motor Threshold [ 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 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 20, 2016)
Change in resting motor threshold [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
Estimated from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, will be used as the primary pharmacodynamic marker of cortical hyperexcitability.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2019)
  • Effect on Short-interval Intracortical Inhibition [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 Hyperpolarizing Threshold Electrotonus (90-100 ms) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Effect on Frequency of Muscle Cramps [ Time Frame: 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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2016)
  • Effects on motor evoked potential (MEP) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from single pulse transcranial magnetic stimulation (TMS)
  • Effects on strength duration time constant [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from threshold tracking nerve conduction studies (TTNCS)
  • Effect on frequency and severity of muscle cramps [ Time Frame: Baseline, Week 4, and Week 8 ]
    Will be assessed using a daily muscle cramps diary and assessment form at Baseline.
  • Effects on cortical silent period [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from single pulse transcranial magnetic stimulation (TMS)
  • Effects on short-interval intracortical inhibition (SICI) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from dual pulse transcranial magnetic stimulation (TMS)
  • Effects on threshold electrotonus [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
    Estimated from threshold tracking nerve conduction studies (TTNCS)
  • Effect on frequency and severity of fasciculations (muscle twitching) [ Time Frame: Baseline, Week 4, and Week 8 ]
    Will be assessed using a daily fasciculations diary and assessment form at Baseline.
Current Other Pre-specified Outcome Measures
 (submitted: November 17, 2019)
  • Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised [ Time Frame: 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 [ Time Frame: Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported ]
    Measure of decline in respiratory muscle strength
Original Other Pre-specified Outcome Measures
 (submitted: May 20, 2016)
  • Evaluate changes in slow vital capacity (SVC) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
  • Evaluate changes in the ALS Functional Rating Scale - revised (ALSFRS-R) [ Time Frame: Screening, Baseline, Week 4, and Week 8 ]
 
Descriptive Information
Brief Title  ICMJE Mexiletine in Sporadic Amyotrophic Lateral Sclerosis
Official Title  ICMJE Effect of Mexiletine on Cortical Hyperexcitability in Sporadic Amyotrophic Lateral Sclerosis (SALS)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Sporadic Amyotrophic Lateral Sclerosis
Intervention  ICMJE
  • Drug: Mexiletine
    Other Name: Mexitil
  • Drug: Placebo
Study Arms  ICMJE
  • Active Comparator: Mexiletine, 300 milligrams
    Mexiletine, 300 milligrams by mouth per day for 4 weeks.
    Intervention: Drug: Mexiletine
  • Active Comparator: Mexiletine, 600 milligrams
    Mexiletine, 600 milligrams by mouth per day for 4 weeks.
    Intervention: Drug: Mexiletine
  • Placebo Comparator: Placebo
    Placebo, by mouth per day for 4 weeks.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 17, 2019)
20
Original Estimated Enrollment  ICMJE
 (submitted: May 20, 2016)
60
Actual Study Completion Date  ICMJE September 30, 2018
Actual Primary Completion Date September 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02781454
Other Study ID Numbers  ICMJE MX-ALS-002
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Michael D Weiss, University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE Massachusetts General Hospital
Investigators  ICMJE
Principal Investigator: Michael Weiss, MD University of Washington
PRS Account University of Washington
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP