Mexiletine in Sporadic Amyotrophic Lateral Sclerosis

NCT02781454 | Completed Phase 2 Results

• 1 other identifier: MX-ALS-002
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 10

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).

Conditions

Sporadic Amyotrophic Lateral Sclerosis

Keywords

SALS; Mexiletine; TMS; NCS

Outcome Measures

Primary Outcomes (1)

• 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.

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported

Secondary Outcomes (10)

• Effect on Short-interval Intracortical Inhibition

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

• Change in Motor Evoked Potential Amplitude

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

• Effect on Cortical Silent Period

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

• Effect on Strength Duration Time Constant

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

• Effect on Depolarizing Threshold Electrotonus (90-100 ms)

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Other Outcomes (2)

• 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

• Change in Slow Vital Capacity

  Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Study Arms (3)

Mexiletine, 300 milligrams

ACTIVE COMPARATOR

Mexiletine, 300 milligrams by mouth per day for 4 weeks.

Drug: Mexiletine

Mexiletine, 600 milligrams

ACTIVE COMPARATOR

Mexiletine, 600 milligrams by mouth per day for 4 weeks.

Drug: Mexiletine

Placebo

PLACEBO COMPARATOR

Placebo, by mouth per day for 4 weeks.

Drug: Placebo

Interventions

Mexiletine DRUG

Also known as: Mexitil

Mexiletine, 300 milligrams; Mexiletine, 600 milligrams

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria.
• Age 18 years or older.
• Symptom onset of weakness or spasticity due to ALS ≤ 60 months prior to Screening Visit.
• Slow vital capacity (SVC) measure ≥50% of predicted for gender, height, and age at the screening visit.
• Must be able to swallow capsules throughout the course of the study, according to Site Investigator judgment.
• Capable of providing informed consent and following trial procedures.
• For TMS: a resting motor threshold defined as 50% of pulses eliciting a motor evoked potential (MEP) of amplitude ≥ 50 µV.
• For TTNCS: median Compound Muscle Action Potential (CMAP) ≥ 1.5 mV.
• 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).
• 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.
• 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.
• 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.

You may not qualify if:

• Invasive ventilator dependence, such as tracheostomy.
• Creatinine level greater than 1.5 mg/dL at screening.
• Serum Glutamic-Oxaloacetic (SGOT/AST) / Serum Glutamic-Pyruvic (SGPT/ALT) 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 30 days prior to Screening Visit.
• 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.
• Metal in the head and neck region, cardiac pacemaker or brain stimulator, cochlear implants, implanted infusion device or personal history of epilepsy.
• Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine.
• Pregnant women or women currently breastfeeding.
• Placement of Diaphragm Pacing System (DPS) device \< 60 days prior to Screening Visit.
• Planned DPS device implantation during study participation

Sponsors & Collaborators

• University of Washington: lead
• Massachusetts General Hospital: collaborator

Study Sites (10)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

University of California, Irvine

Orange, California, 92868, United States

Location

Augusta University

Augusta, Georgia, 30912, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Columbia Universtiy Medical Center

New York, New York, 10032, United States

Location

Pennsylvania State Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Related Links

• Northeast ALS Consortium Website

MeSH Terms

Conditions

Amyotrophic lateral sclerosis 1

Interventions

Mexiletine

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Phenyl Ethers; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Results Point of Contact

• Title: Dr. Michael D. Weiss
• Organization: University of Washington

mdweiss@uw.edu

206-598-7688

Study Officials

• Michael Weiss, MD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Department of Neurology

Study Record Dates

• First Submitted: May 10, 2016
• First Posted: May 24, 2016
• Study Start: October 1, 2016
• Primary Completion: September 30, 2018
• Study Completion: September 30, 2018
• Last Updated: December 5, 2019
• Results First Posted: December 5, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (10)