Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multisystem disease caused by an unstable, abnormal expansion of a trinucleotide repeat [CTG]n on chromosome 19. DM1 is the most common form of muscular dystrophy and has a prevalence of less than 100,000 cases in the United States. The symptoms of DM1 are widespread. Distal muscle weakness in the arms and legs, along with facial weakness and grip myotonia may occur along with impaired ambulation, unsteadiness on arising from a chair, difficulty with fine finger movements, trouble swallowing, gastrointestinal hypomotility, musculoskeletal pain, and a reduction in health-related quality-of-life. Physiological myotonia (or muscle locking) is thought to significantly contribute to many of these clinical symptoms;especially patient relevant impairment of ambulation. To date, there has never been a large scale, extended, controlled treatment trial of myotonia in DM1. Two recent, short-term, FDA funded, 7 week double-blind, placebo-controlled, crossover trials of mexiletine (150 mg TID vs. placebo TID;200mg TID vs. placebo TID) have been performed in our Neuromuscular Disease Center. These studies demonstrated both encouraging results and a preferential dosage schedule. Each trial involved 20 moderately affected DM1 patients. There were no significant side effects with either dose of mexiletine, and a reduction in grip myotonia was demonstrated. Compared to the 200 mg TID dosage, the 150 mg TID dose produced a similar level of myotonia reduction with an added benefit of improved peak grip force. There is a clear need for a longer-term trial of mexiletine to establish its safety and efficacy as a therapy for DM1. In order to determine if mexiletine is safe and effective for long-term treatment (6 months) in improving ambulation and reducing myotonia in DM1 we propose a 6 month, randomized, double-blind, placebo- controlled, trial of mexiletine (mexiletine 150 mg TID vs. placebo TID). Each arm of the trial (mexiletine and placebo) will involve 20 moderately affected patients with DM1. Our primary goal is to determine if mexiletine is well tolerated and able to improve six minute walk distances over 6 months of therapy. Our secondary goals are to determine if mexiletine reduces hand myotonia, increases muscle strength (grip strength, quantitative myometry and manual muscle testing), improves function (timed function tests), and/or improves DM1-specific health-related quality-of-life. We anticipate that this study has the potential to establish (or discourage) a new indication for the use of mexiletine.
Myotonic dystrophy type 1, the most common adult muscular dystrophy, causes a gait disturbance and progressive weakness that is often aggravated by coexisting myotonia (delayed muscle relaxation and muscle stiffness). Difficulty with ambulation has been identified by DM1 patients as one of the most important disease-specific limitations.[Heatwole et al, 2009] A safe, effective, FDA- approved, long-term treatment of myotonia is needed to improve ambulation and muscle function for these patients. The clinical trial described in this Orphan Product Development Grant application will demonstrate if the antimyotonia drug mexiletine is able to improve patient ambulation while improving function and reducing myotonia.