Mexiletine for the Treatment of Muscle Cramps in ALS

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.

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