Mexiletine for the Treatment of Muscle Cramps in ALS

• ClinicalTrials.gov Identifier: NCT01811355
• Recruitment Status: Completed
• First Posted: March 14, 2013
• Results First Posted: June 27, 2017
• Last Update Posted: August 28, 2017
• Sponsor: Bjorn Oskarsson, MD
• Collaborators: University of California, Davis; ALS Association
• Information provided by (Responsible Party): Bjorn Oskarsson, MD, University of California, Davis

Study Description

Brief Summary:

The purpose of this study is to determine if mexiletine is effective for the treatment of muscle cramps in Amyotrophic Lateral Sclerosis (ALS).

Condition or disease	Intervention/treatment	Phase
Muscle Cramps in Amyotrophic Lateral Sclerosis	Drug: Mexiletine; Drug: Placebo	Phase 4

Detailed Description:

Background:

Many ALS patients suffer from painful muscle cramps, but unfortunately we do not have any medication proven to help muscle cramps in ALS. Reducing the pain caused by cramps - which can be debilitating - could help people living with ALS.

Muscle cramps are sudden, painful, and involuntary contractions of a muscle. They are caused by nerve dysfunction. When we examine nerves and muscles electrically, we see cramps as bursts of high-frequency (up to150 Hz) firing of the motor nerve cells. Cramps in ALS are believed to be the result of an increase of persistent sodium currents in the sick lower motor nerve cells.

A medication called Quinine was for many years the commonly used drug for controlling cramps in ALS, but the FDA has advised against its use for cramps because of its potential risks (e.g., death). Today there is no agreement on how to treat cramps in the ALS. The American Academy of Neurology recently encouraged further studies of the treatment of muscle cramps and suggested lidocaine as one of a few drugs of special interest.

Mexiletine:

Mexiletine is a medication closely related to lidocaine that can be taken by mouth (instead of being injected). Mexiletine stops the type of sodium currents that are thought to cause muscle cramps. Mexiletine is a relatively older medication that has been extensively studied in humans. It has been shown to reduce the electrical measures of muscle cramps for other disease conditions. For example, in patients with another severe nerve disease - Machado-Joseph disease (SCA3) - mexiletine treatment led to a decrease in the average number of muscle cramps from 24 to 3 cramps per month.. The safety profile of mexiletine is good, with the most frequent side effects being nausea or other abdominal symptoms. These side effects are rare at the doses (300 mg/day) used in this study. In patients with normal heart function, mexiletine has a minimal effect on heart rhythm. In previous clinical trials, no subject developed any serious heart rate problem.

Experimental Plan:

Using multiple sites within the State of California we will quickly enroll a small number (N=30) of ALS patients with severe muscle cramps. The study is a double-blinded, placebo controlled (i.e., the investigator and the participant does not know if the pills contain mexiletine or placebo), crossover (all subjects receive two weeks of mexiletine and two weeks of placebo) study.

After a one week run in, participants will be evaluated on their ability to fill out the cramp diary. Participants who filled out their diary will be randomly assigned to either mexiletine or placebo for their first two weeks. For the first three days of each 2-week period, one 150mg capsule will be taken at bed time. For day 4 to 14 one capsule twice per day will be taken. Each treatment period will be 2 weeks with an intervening 1 week washout period - for a total study length of 6 weeks. Safety will be monitored with liver function studies and EKG's.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Mexiletine for the Treatment of Muscle Cramps in ALS
• Study Start Date: May 2013
• Actual Primary Completion Date: March 2016
• Actual Study Completion Date: May 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Mexiletine; Mexiletine, capsule, 150mg, PO BID, 14 days	Drug: Mexiletine; Sodium channel blocker; Other Name: Mexetil
Placebo Comparator: Placebo; Placebo, capsule, PO BID, 14 days	Drug: Placebo; Placebo; Other Name: Sugar pill

Outcome Measures

Primary Outcome Measures :

1. Daily Muscle Cramps [ Time Frame: 6 weeks ]
   The average of the daily recording of number of muscle cramps that occurred in the last 24 hours- over a 6 week period.
2. Cramp Severity [ Time Frame: 6 weeks ]
   Daily cramp severity was rated on the 100-unit visual analog scale. Scores ranged from 0 to 100, with 100 being the greatest amount of cramp severity

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 89 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• ALS diagnosed according to El Escorial criteria (Awaji version) as: Possible, Probable, or Definite.
• Experiencing cramps as a moderate or severe symptom as defined by willingness to take a medication for the symptom
• ≥2 cramps per week during run in week
• Life expectancy > 6 months, estimated by clinician
• Able to take drug capsule by mouth
• No significant EKG abnormality on screening
• aspartate aminotransferase / alanine aminotransferase <2x upper limit of normal measured at screening
• Having successfully filled out the cramp diary and cramp and fasciculation scales on six out of the last seven days of run in period

Exclusion Criteria:

• Inability to communicate by telephone or email
• Allergy/ known sensitivity to mexiletine
• Prior use of mexiletine
• AV block unless subject has pacemaker
• Cardiac arrhythmia
• Prior myocardial infarction
• Other significant EKG abnormality
• Liver disease
• History of leucopenia (WBC <3,500/mm3)
• Epilepsy
• Other serious and unstable medical condition
• Pregnant woman
• Breastfeeding woman
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
• Use of quinidine (alone or as a component of Nuedexta®) during the study
• Inability or unwillingness of subject to give written informed consent
• Woman of childbearing potential, not willing to use at least two approved methods of contraception
• Use of a prohibited medication during study

Contacts and Locations

Locations

United States, California

UCD Telehealth Network - Lake Almanor Clinic

Chester, California, United States, 96020

UCSD Department of Neurosciences ALS Clinical Trials (ACT) Program

La Jolla, California, United States, 92093

UCLA Neuromuscular Research Program

Los Angeles, California, United States, 90095

UCD Telehealth Network

Multiple Locations, California, United States, Various

UC Irvine Health ALS & Neuromuscular Center

Orange, California, United States, 92868

UC, Davis Medical Center ALS Clinic

Sacramento, California, United States, 95817

Sponsors and Collaborators

Bjorn Oskarsson, MD

University of California, Davis

ALS Association

Investigators

• Principal Investigator: Bjorn Oskarsson, MD; UC Davis

More Information

• Responsible Party: Bjorn Oskarsson, MD, Assistant Professor of Clinical Neurology, University of California, Davis
• ClinicalTrials.gov Identifier: NCT01811355
• Other Study ID Numbers: 378164
• First Posted: March 14, 2013
• Results First Posted: June 27, 2017
• Last Update Posted: August 28, 2017
• Last Verified: July 2017

Keywords provided by Bjorn Oskarsson, MD, University of California, Davis:

Muscle cramps; Cramp; ALS; Amyotrophic Lateral Sclerosis; Lou Gehrig's disease; Motor Neuron Disease; MND

Additional relevant MeSH terms:

Muscle Cramp; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Spasm; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Manifestations; Neurologic Manifestations; Mexiletine; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action