Back to resultsMexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS) (MX-ALS-001)
Primary Purpose
Sporadic Amyotrophic Lateral Sclerosis
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Mexiletine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Sporadic Amyotrophic Lateral Sclerosis focused on measuring SALS, Mexiletine, Safety
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.
Sites / Locations
- UCLA, Neuromuscular Research Center
- University of Iowa
- University of Kansas Medical Center
- Massachusetts General Hospital
- University of Massachusetts (Worcester) Memorial Medical Center
- Washington University Medical School
- SUNY Upstate Medical Center
- Penn State Hershey Medical Center
- University of Texas Southwestern Medical Center at Dallas
- University of Washington Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Active Comparator
Placebo Comparator
Arm Label
Mexiletine, 300 milligrams
Mexiletine, 900 milligrams
Placebo
Arm Description
Mexiletine, 300 milligrams by mouth per day for 12 weeks.
Mexiletine, 900 milligrams by mouth per day for 12 weeks.
Placebo, by mouth per day for 12 weeks.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Trough Plasma Concentration (Cmin) of Mexiletine
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Peak Plasma Concentration (Cmax) of Mexiletine
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.
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Mean Cerebrospinal Fluid (CSF)/Plasma Ratio
The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma.
Mean Weekly Cramp Frequency
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.
Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12
Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12
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.
Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12
Full Information
NCT ID
NCT01849770
First Posted
May 6, 2013
Last Updated
September 27, 2021
Sponsor
University of Washington
1. Study Identification
Unique Protocol Identification Number
NCT01849770
Brief Title
Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS)
Acronym
MX-ALS-001
Official Title
A Safety and Tolerability Study of Mexiletine in Patients With Sporadic Amyotrophic Lateral Sclerosis (SALS)
Study Type
Interventional
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
July 2013 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
August 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sporadic Amyotrophic Lateral Sclerosis
Keywords
SALS, Mexiletine, Safety
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
75 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Mexiletine, 300 milligrams
Arm Type
Active Comparator
Arm Description
Mexiletine, 300 milligrams by mouth per day for 12 weeks.
Arm Title
Mexiletine, 900 milligrams
Arm Type
Active Comparator
Arm Description
Mexiletine, 900 milligrams by mouth per day for 12 weeks.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo, by mouth per day for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Mexiletine
Other Intervention Name(s)
Mexitil
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Percentage of Participants That Discontinued Study Drug
Description
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.
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.
Secondary Outcome Measure Information:
Title
Trough Plasma Concentration (Cmin) of Mexiletine
Description
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Time Frame
Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6)
Title
Peak Plasma Concentration (Cmax) of Mexiletine
Description
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Time Frame
Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6)
Title
Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma.
Description
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Time Frame
Week 6 Visit (up to 6 hours post dose)
Title
Mean Cerebrospinal Fluid (CSF)/Plasma Ratio
Description
The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma.
Time Frame
Week 6 Visit (up to 6 hours post dose)
Title
Mean Weekly Cramp Frequency
Time Frame
Week 3-12, post titration of study medication
Title
Maximal Pain Severity
Description
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.
Time Frame
Weeks 3-12, post titration of study medication
Title
Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12
Time Frame
Week 3-12, post titration of study medication
Title
Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12
Time Frame
Week 3-12, post titration of study medication
Title
Mean Pain Severity
Description
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.
Time Frame
Weeks 3-12, post titration of study medication
Title
Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12
Time Frame
Week 3-12, post titration of study medication
Other Pre-specified Outcome Measures:
Title
Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score
Description
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.
Time Frame
Week 0, Week 2, Week 6, Week 12 (or Early Termination Date), and Week 16
Title
Change in Slow Vital Capacity (SVC) Score
Description
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.
Time Frame
Week 0, Week 6, and Week 12 (or Early Termination Date)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael D Weiss, MD
Organizational Affiliation
University of Washington Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA, Neuromuscular Research Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Massachusetts (Worcester) Memorial Medical Center
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
Washington University Medical School
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
SUNY Upstate Medical Center
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Penn State Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
University of Texas Southwestern Medical Center at Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390-8897
Country
United States
Facility Name
University of Washington Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
12. IPD Sharing Statement
Links:
URL
http://www.alsconsortium.org/
Description
Northeast ALS Consortium Website
URL
http://alsn.mda.org/news/multicenter-trial-test-safety-mexiletine-sporadic-als
Description
Muscular Dystrophy Association (MDA) Website
Learn more about this trial
Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (SALS)
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