Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS) (MX-ALS-001)

• ClinicalTrials.gov Identifier: NCT01849770
• Recruitment Status: Completed
• First Posted: May 8, 2013
• Results First Posted: October 12, 2015
• Last Update Posted: September 29, 2021
• Sponsor: University of Washington
• Information provided by (Responsible Party): Michael D Weiss, University of Washington

Tracking Information

• First Submitted Date: May 6, 2013
• First Posted Date: May 8, 2013
• Results First Submitted Date: July 7, 2015
• Results First Posted Date: October 12, 2015
• Last Update Posted Date: September 29, 2021
• Study Start Date: July 2013
• Actual Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 10, 2015)

Percentage of Participants That Discontinued Study Drug [ Time Frame: Screening, Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Adverse Events will be assessed via telephone Weeks 1, 10, and 16. ]

Information on adverse effects of mexiletine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results.

Original Primary Outcome Measures (submitted: May 7, 2013)

To evaluate the safety and tolerability of mexiletine at 2 doses (300 milligrams mexiletine and 900 milligrams mexiletine) as assessed by the number of adverse events experienced over time. [ Time Frame: Screening, Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Adverse Events will be assessed via telephone Weeks 1, 10, and 16. ]

Information on adverse effects of mexiletine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results.

Current Secondary Outcome Measures (submitted: September 10, 2015)

• Trough Plasma Concentration (Cmin) of Mexiletine [ Time Frame: Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) ]
  Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
• Peak Plasma Concentration (Cmax) of Mexiletine [ Time Frame: Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) ]
  Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
• Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. [ Time Frame: Week 6 Visit (up to 6 hours post dose) ]
  Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
• Mean Cerebrospinal Fluid (CSF)/Plasma Ratio [ Time Frame: Week 6 Visit (up to 6 hours post dose) ]
  The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma.
• Mean Weekly Cramp Frequency [ Time Frame: Week 3-12, post titration of study medication ]
• Maximal Pain Severity [ Time Frame: Weeks 3-12, post titration of study medication ]
  At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily.
• Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 [ Time Frame: Week 3-12, post titration of study medication ]
• Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 [ Time Frame: Week 3-12, post titration of study medication ]
• Mean Pain Severity [ Time Frame: Weeks 3-12, post titration of study medication ]
  At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily.
• Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 [ Time Frame: Week 3-12, post titration of study medication ]

Original Secondary Outcome Measures (submitted: May 7, 2013)

• To evaluate mexiletine pharmacokinetic parameters in serum (trough concentration, peak concentration, time to peak concentration, elimination half-life, and area under the concentration time curve (AUC)). [ Time Frame: Week 6 Visit up to 6 hours post dose ]
  Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
• To evaluate investigate mexiletine pharmacokinetic parameters in cerebral spinal fluid (trough concentration, peak concentration, time to peak concentration, elimination half-life, and area under the concentration time curve (AUC)). [ Time Frame: Week 6 Visit up to 6 hours post dose ]
  Subjects will have a single lumbar puncture done to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.

Current Other Pre-specified Outcome Measures (submitted: September 10, 2015)

• Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score [ Time Frame: Week 0, Week 2, Week 6, Week 12 (or Early Termination Date), and Week 16 ]
  The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival.
• Change in Slow Vital Capacity (SVC) Score [ Time Frame: Week 0, Week 6, and Week 12 (or Early Termination Date) ]
  The vital capacity (VC) (percent of predicted normal) will be determined, using the slow VC method. The SVC can be measured using conventional spirometers that have had a calibration check prior to subject testing. A printout from the spirometer of all SVC trials will be retained.

Original Other Pre-specified Outcome Measures (submitted: May 7, 2013)

• To evaluate the effect of mexiletine at 2 doses (300 milligrams and 900 milligrams) on the number (frequency) and intensity (pain) of muscle cramps experienced over time. [ Time Frame: Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Muscle cramps will be assessed via telephone Weeks 1 and 10 ]
  study drug early. Muscle cramps will be assessed via telephone Weeks 1 and 10 Description: At the Baseline Visit, subjects will be asked to recount the number of muscle cramps experienced in the previous 24 hours and the total number of cramp experienced in the previous 30 days. Subjects will also be asked to recount the maximum pain experienced with a muscle cramp in the previous 24 hours and the maximum pain experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp frequency and intensity at home, daily.
• Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score [ Time Frame: Screening, Baseline Visit Pre-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. The ALSFRS-R will be assessed via telephone Week 16. ]
  The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival.
• Change in Slow Vital Capacity (SVC) Score [ Time Frame: Screening Visit, Baseline Visit Pre-Dose, Week 6 and 12, and at the Final Safety Visit for subject's who discontinue early. ]
  The vital capacity (VC) (percent of predicted normal) will be determined, using the slow VC method. The SVC can be measured using conventional spirometers that have had a calibration check prior to subject testing. A printout from the spirometer of all SVC trials will be retained.

Descriptive Information

• Brief Title: Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS)
• Official Title: A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)
• Brief Summary: The purpose of this research is to find out if mexiletine is safe and effective in people with Amyotrophic Lateral Sclerosis (ALS). In this trial, participants will be taking either 300 milligrams per day of mexiletine, 900 milligrams per day of mexiletine or placebo (non-active study drug). The safety and efficacy of these doses will be compared to see if one dose is better than the other.
• 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sporadic Amyotrophic Lateral Sclerosis

Intervention

• Drug: Mexiletine
  Other Name: Mexitil
• Drug: Placebo

Study Arms

• Active Comparator: Mexiletine, 300 milligrams
  Mexiletine, 300 milligrams by mouth per day for 12 weeks.
  Intervention: Drug: Mexiletine
• Active Comparator: Mexiletine, 900 milligrams
  Mexiletine, 900 milligrams by mouth per day for 12 weeks.
  Intervention: Drug: Mexiletine
• Placebo Comparator: Placebo
  Placebo, by mouth per day for 12 weeks.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 10, 2015): 75
• Original Estimated Enrollment (submitted: May 7, 2013): 60
• Actual Study Completion Date: August 2014
• Actual Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Sporadic Amyotrophic Lateral Sclerosis (SALS) diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
• Age 18 years or older.
• Disease duration ≤ 36 months from ALS symptom onset.
• Capable of providing informed consent and following trial procedures.
• Subjects must not have taken riluzole for at least 30 days or be on a 50 milligrams twice daily dose of riluzole for at least 60 days prior to randomization (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 randomization or be on a stable dose for at least 60 days prior to randomization.
• 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.
• Slow vital capacity (SVC) measure greater than or equal to 50% of predicted for gender, height, and age at the screening visit.
• Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (for example, no bleeding disorder, allergy to local anesthetics, a skin infection at or near the LP site, or evidence of high intracranial pressure).
• Must be able to swallow capsules throughout the course of the study, according to Principal Investigator (PI) judgment.
• Must have a caregiver assist with dispensing the study drug.

Exclusion Criteria:

• Invasive ventilator dependence, such as tracheostomy.
• Creatinine level greater than 1.5 milligram/deciliter.
• Serum glutamic oxaloacetic transaminase or (aspartate transaminase) / serum glutamic pyruvic transaminase (alanine aminotransferase) 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 60 days prior to Baseline Visit.
• Exposure to any other experimental agent (off-label use or investigational) including high dose creatine (greater than 10 grams a day) within 30 days prior to Baseline Visit.
• Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
• Pregnant women or women currently breastfeeding.
• Placement of Diaphragm Pacing System (DPS) device less than 60 days prior to Baseline Visit.
• Planned DPS device implantation after Baseline Visit.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01849770
• Other Study ID Numbers: 43708
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Michael D Weiss, University of Washington
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Washington
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Michael D Weiss, MD; University of Washington Medical School

• PRS Account: University of Washington
• Verification Date: September 2021