ARTICLE IN BRIEF
Mexiletine, a drug developed in the 1970s to treat abnormal heart rhythms, was found to be effective in alleviating symptoms of myotonia in a small, randomized placebo-controlled trial.
An old heart drug, mexiletine, shelved for lack of use has been brushed off and put to work for the treatment of patients with myotonia, a genetic condition linked to sodium and chloride defects. And while neurologists have been prescribing the drug for several years — since word spread of its effectiveness in a few case reports — a team of doctors and scientists now have conducted a randomized study of the drug. Preliminary evidence suggests it is effective.
Mexiletine was developed in the 1970s to treat abnormal heart rhythms and was bypassed as newer and better drugs came along. It works on sodium channels in muscle. In vitro and animal models suggest that it reduces muscle fiber excitability at the muscle sodium channels.
In the Oct. 3 Journal of the American Medical Association (JAMA), Richard J. Barohn, MD, and his colleagues in the Consortium for Clinical Investigation of Neurologic Channelopathies, reported on their findings from a randomized, double-blind, placebo-controlled crossover study at seven neuromuscular referral centers in four countries. In less than three years, they were able to enroll 59 patients with nondystrophic myotonia and test them on and off the drug for a month at a time. (There was a washout period during the two study arms.)
While they showed that the drug reduced the stiffness that is often the main complaint of patients, the study is being heralded simply because they were able to rally enough patients with this rare disease to put a drug to the test. “Now, we have evidence-based medicine to show that mexiletine helps patients,” said Dr. Barohn, professor and chair of neurology at the University of Kansas Medical Center.
“When we formed this consortium with Robert Griggs, MD, [professor of neurology, medicine, pathology and laboratory medicine, and pediatrics at the University of Rochester School of Medicine and Dentistry] we wanted to do a treatment trial,” explained Dr. Barohn.
The study team decided to study mexiletine but first they needed to design a way to document muscle stiffness, which is generally subjective and hard to measure. But they realized that patient self-reports would actually work to separate out whether someone is feeling stiff and weak on or off a given treatment.
In 2002, they started the process of identifying patients with nondystrophic myotonia and learning how to study their symptoms and signs of their muscle disorder, which was made possible through the Rare Disease Clinical Research Network, which is funded by the National Institutes of Health. In 2008, they obtained an additional grant from the FDA Office of Orphan Products Development to study mexiletine. With neurologists around the world recruiting their myotonia patients, from late 2008 to early 2011 they found enough patients to conduct the study.
“This is a good example of the powers of a consortium and a repurposing of an old drug,” Dr. Barohn said. “We hope it is a model on how to do rare disease research.”
THE TRIAL DESIGN, RESULTS
Patients were blinded and randomized to take a placebo capsule or an oral dose of 200 mg of mexiletine three times a day for a month, followed by a one week washout phase and then were crossed over to take the other intervention for a month. Patients provided a daily voice recorded diary of their muscle stiffness, pain, weakness and fatigue. They were also assessed for handgrip and quality of life measures. The scores went from a scale of 1 for minimal symptoms to 9 for worst ever experienced.
According to the study analysis, there was a statistically significant interaction between the treatment and the reduction of stiffness, which was the primary endpoint in the study: a mean of 2.5 for mexiletine and 4.21 for placebo (p = .001) for the first month and 1.60 for mexiletine and 5.27 for those on placebo during the second month (p = .04).
The most common adverse effect was gastrointestinal in about 15 to 20 percent of patients while they were taking mexiletine (nine versus one on placebo). Two participants, one in each group, experienced transient cardiac effects that did not require stopping the study; the investigators determined that the adverse events were not related to the study.
“We showed a dramatic effect when patients were on the drug compared to when they were not taking it,” said Dr. Barohn. “It helped patients across the board.”
“This will give neurologists more confidence using it as a first-line therapy,” Dr. Barohn added. There are no treatments federally approved for the rare condition, which affects fewer than one in 100,000 people. “It is prescribed off label.”
AN ACHIEVEMENT, WITH SOME LIMITATIONS
“It's hard to pull off these kinds of studies,” said Eric P. Hoffman, PhD, professor and chair in the department of integrative systems biology at George Washington University, who identified the first myotonia gene in 1991. Dr. Hoffman wrote an accompanying editorial in JAMA with Henry J. Kaminski, MD, chairman of neurology at George Washington University.
The problem with the study, he explained, is that recruitment included patients with defects in the sodium or chloride channels. And there is great individual variability in the symptoms, which makes it hard to really know if a drug is making a difference. Still, he said: “It is an old drug with a decent effect.”
“This is a well-designed trial of orphan diseases with genetic and clinical heterogeneity, and such trials are difficult to conduct,” Dr. Hoffman and Dr. Kaminski wrote in their editorial. “The rarity of these disorders makes recruitment for therapeutic trials a challenge, whereas the heterogeneity of these disorders makes targeting specific underlying disease mechanisms and specific clinical manifestations problematic. A substantial subset of patients reported infrequent episodes of myotonia at baseline, making it challenging to detect drug-related improvements.”
They said that the interactive voice response system (IVR) also proved an effective tool to accumulate symptom data for analysis. “The system eliminated need for cumbersome paper diaries, which are burdensome for most participants and research coordinators. The IVR system also provided a clear time stamp for documentation, and it may have improved adherence due to reminder calls.” During the study, there was a 90 percent adherence to the reporting system.
They added that the length of the study may prove to be a limitation. It was “too short to be confident of the long-lasting effects of mexiletine and the trial was too small and too brief for determination of safety in these conditions.”
“Many neurologists already use this drug,” added Dr. Kaminski. “Now, a rigorous (but short) trial supports its use.”