Patients with nondystrophic myotonia, a rare genetic muscle disorder, often have problems with debilitating muscle stiffness, fatigue, and sometimes even episodes of paralysis. Now, these patients have new help: a drug called mexiletine, normally used to treat heart disorders. With assistance from NIH’s Rare Diseases Clinical Research Network (RDCRN) and Clinical and Translational Science Awards (CTSA) program, researchers at seven institutions in four countries collaborated to demonstrate in a clinical trial that the heart drug is effective in treating patients with this rare disease.
In a study published in JAMA in October 2012, a research team led by Jeffrey Statland, M.D., a neurologist at the University of Rochester Medical Center, found that mexiletine significantly improved patient-reported muscle stiffness. Jaya Trivedi, M.D., at UT Southwestern Medical Center in Dallas, one of the authors of the study, said, “Nondystrophic myotonia is not as debilitating as some forms of muscular dystrophy that lead to a wheelchair-confined state, but the symptoms it produces significantly impair patients’ daily living activities.” Symptoms may be triggered by cold, exercise or other exposures. Last summer, she said, she saw a 14-year-old boy with the disease who plays baseball, but if he isn’t warmed up, he can’t even run to first base.
Rare diseases such as this one are a focus of the RDCRN’s Consortium for Clinical Investigation of Neurologic Channelopathies (CINCH). The RDCRN, which is managed by NCATS’ Office of Rare Diseases Research (ORDR) and supported by several NIH Institutes and Centers, facilitates collaboration among experts to explore the natural history, epidemiology, diagnosis and treatment of nearly 100 rare diseases. The RDCRN consists of a Data Management and Coordinating Center and 17 distinct clinical research consortia ― each of which studies a minimum of three related diseases. For each disease, consortia members work together to implement a natural history study that describes the disease and its symptoms over time, then they carry out other studies such as drug or other treatment trials.
CINCH researchers already had completed a natural history study of nondystrophic myotonia, and the next step was a study of mexiletine, a generic drug normally used to treat cardiac arrhythmias or seriously irregular heartbeats. Since the 1980s, doctors have prescribed mexiletine off-label for nondystrophic myotonia, and it seemed to help some patients. But since the disease is so uncommon, no one had been able to study the drug in enough patients to find out if it actually worked in a large study.
Through the RDCRN, researchers were able to find the 60 patients needed for the evaluation. The RDCRN has centers in multiple locations around the world and provides tools and resources to support a broad, international collaboration.
Patients in this study were at four sites in the United States, and at one site each in Canada, the United Kingdom, and Italy. To collect and manage the study data from the seven sites, the research team used the RDCRN’s Data Management Coordinating Center at the University of South Florida. Additionally, each of the four U.S. sites has a Clinical and Translational Science Award that provides resources and services to medical researchers. For this study, the team used a variety of CTSA resources for lab tests, electrocardiograms, muscle tests, and pharmacy services. Primary funding for the study was provided by the U.S. Food and Drug Administration’s Office of Orphan Products Development, and by NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
Based upon the earlier natural history study, researchers identified some potential study participants, but more were needed. Richard Barohn, M.D., CINCH co-investigator and principal investigator for the CTSA grant at the University of Kansas Medical Center, took advantage of the CTSA’s resources for recruiting participants. “It’s a challenge to find these patients,” he said. “The CTSA helps get the word out to local doctors about the study.”
During the double-blind study, patients took either mexiletine or a placebo for four weeks, and then had a one-week break followed by four weeks of the opposite intervention. Mexiletine improved muscle stiffness in these patients significantly, but, since the drug has some side effects, the research team is continuing to look for other ways to treat people with nondystrophic myotonia.
According to an editorial in the same issue of JAMA as the published research, the study was hailed as a “triumph for rare disease networks.” It also indicated that the study was completed in only 28 months, which was “noteworthy for a group of diseases with a worldwide estimated prevalence of one per 100,000.”
ORDR Director Stephen Groft, Pharm.D., said that the mexiletine story is a perfect example of how NCATS facilitates rare disease research: “Responding to the needs of patients who have one of the estimated 6,800 rare diseases known today is paramount. We were able to leverage diverse resources to complete a successful study that will make a real difference in the lives of patients with nondystrophic myotonia.”
Meanwhile, the drug has made a difference in the life of that young patient of Dr. Trivedi’s. “When he takes this drug, he performs better in baseball, which is important to him,” she said.
Posted December 2012