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

Tracking Information

• First Submitted Date: March 6, 2013
• First Posted Date: March 14, 2013
• Results First Submitted Date: April 3, 2017
• Results First Posted Date: June 27, 2017
• Last Update Posted Date: August 28, 2017
• Study Start Date: May 2013
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 28, 2017)

• 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.
• 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

Original Primary Outcome Measures (submitted: March 12, 2013)

Cramp diary [ Time Frame: Daily during the 6 week study ]

Daily recording of number of muscle cramps that occurred in the last 24 hours.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mexiletine for the Treatment of Muscle Cramps in ALS
• Official Title: Mexiletine for the Treatment of Muscle Cramps in ALS
• 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).

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 Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Muscle Cramps in Amyotrophic Lateral Sclerosis

Intervention

• Drug: Mexiletine
  Sodium channel blocker
  Other Name: Mexetil
• Drug: Placebo
  Placebo
  Other Name: Sugar pill

Study Arms

• Active Comparator: Mexiletine
  Mexiletine, capsule, 150mg, PO BID, 14 days
  Intervention: Drug: Mexiletine
• Placebo Comparator: Placebo
  Placebo, capsule, PO BID, 14 days
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 23, 2017): 23
• Original Estimated Enrollment (submitted: March 12, 2013): 30
• Actual Study Completion Date: May 2016
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 89 Years (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: NCT01811355
• Other Study ID Numbers: 378164
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bjorn Oskarsson, MD, University of California, Davis
• Original Responsible Party: Same as current
• Current Study Sponsor: Bjorn Oskarsson, MD
• Original Study Sponsor: Same as current

Collaborators

• University of California, Davis
• ALS Association

Investigators

• Principal Investigator: Bjorn Oskarsson, MD; UC Davis

• PRS Account: University of California, Davis
• Verification Date: July 2017