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

A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)

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.

Study Overview

• Status: Completed
• Conditions: Sporadic Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Mexiletine

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 Recent unpublished studies in the laboratory of Dr.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
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA, Neuromuscular Research Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts (Worcester) Memorial Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical School
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
  • Texas
    • Dallas, Texas, United States, 75390-8897
      • University of Texas Southwestern Medical Center at Dallas
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mexiletine, 300 milligrams; Mexiletine, 300 milligrams by mouth per day for 12 weeks.	Drug: Mexiletine; Other Names: Mexitil
Active Comparator: Mexiletine, 900 milligrams; Mexiletine, 900 milligrams by mouth per day for 12 weeks.	Drug: Mexiletine; Other Names: Mexitil
Placebo Comparator: Placebo; Placebo, by mouth per day for 12 weeks.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants That Discontinued Study Drug	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough Plasma Concentration (Cmin) of Mexiletine	Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.	Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6)
Peak Plasma Concentration (Cmax) of Mexiletine	Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.	Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6)
Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma.	Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.	Week 6 Visit (up to 6 hours post dose)
Mean Cerebrospinal Fluid (CSF)/Plasma Ratio	The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma.	Week 6 Visit (up to 6 hours post dose)
Mean Weekly Cramp Frequency		Week 3-12, post titration of study medication
Maximal Pain Severity	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.	Weeks 3-12, post titration of study medication
Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12		Week 3-12, post titration of study medication
Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12		Week 3-12, post titration of study medication
Mean Pain Severity	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.	Weeks 3-12, post titration of study medication
Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12		Week 3-12, post titration of study medication

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score	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.	Week 0, Week 2, Week 6, Week 12 (or Early Termination Date), and Week 16
Change in Slow Vital Capacity (SVC) Score	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.	Week 0, Week 6, and Week 12 (or Early Termination Date)

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Northeast ALS Consortium Website
• Muscular Dystrophy Association (MDA) Website

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: May 6, 2013
• First Submitted That Met QC Criteria: May 7, 2013
• First Posted (Estimate): May 8, 2013

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Mexiletine; SALS
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Mexiletine
• Other Study ID Numbers: 43708