Tadalafil in Becker Muscular Dystrophy

Overview

Summary for Patients: This study, funded by the Muscular Dystrophy Association, is intended to build on recent findings published in the journal Nature showing beneficial effects of tadalafil (also known as Cialis) in mice with an animal version of Duchenne and Becker muscular dystrophies. Only two doses of tadalafil improved muscle blood flow, allowing the dystrophic mice to perform more exercise with less muscle injury. This new short-term clinical trial will move the testing from animals to human patients with Becker muscular dystrophy and examine the effects of acute tadalafil dosing on muscle blood flow during a bout of exercise. Patients will take two doses of tadalafil prior to exercising. Then doctors will measure whether muscles receive increased blood flow and therefore are better protected during exercise. Scientific Hypothesis: In patients with Becker muscular dystrophy (particularly those with dystrophin gene mutations between exons 41-46), loss of sarcolemmal nitric oxide synthase engenders functional muscle ischemia and thus muscle edema after an acute bout of exercise. The investigators further hypothesize that PDE5A inhibition, which boosts nitric oxide-cGMP signaling, constitutes an effective new countermeasure for these patients.

There are 2 phases to this research project: (1) an initial baseline study to compare patients with Becker muscular dystrophy against healthy control subjects, and (2) a subsequent brief treatment trial only in the muscular dystrophy patients (healthy controls will not participate in this second phase of the study). The baseline study involves an intake history, physical examination, and phlebotomy for blood chemistries and DNA followed by (a) MRI scans of the forearm muscles before and after a brief bout of handgrip exercise approximately 1-1.5 hours to complete), and (b) non-invasive forearm blood flow studies (Near Infrared Spectroscopy, Doppler Ultrasound) before and after a brief bout of handgrip exercise (approximately 3-5 hours to complete). Blood flow studies will be performed with the subject's lower body enclosed in an airtight chamber. Blood flow and oxygen delivery to the forearm muscles will be measured before and during application of lower body negative pressure at rest and during handgrip exercise. Lower body negative pressure simulates the blood flow changes that normally occur when a person sits up after lying down. The results of the baseline study will determine which patients meet preset eligibility criteria to participate in the medication phase of the study. These criteria include (1) normal kidney and liver function tests and normal BNP levels (the latter to exclude heart failure), and (2) abnormal MRI and blood flow responses to handgrip exercise. Eligible patients will be asked to repeat the above laboratory procedures on two more study days: one day after receiving 2 pills of tadalafil (a PDE5A inhibitor that is longer-lasting than Viagra) and another day after receiving 2 placebo pills. Study procedures can be broken up into two separate days for scheduling purposes and/or to avoid fatigue. Patients completing the trial will receive both study medications and the order will be random. In summary, healthy control subjects will only undergo the baseline study whereas Becker muscular dystrophy patients completing all phases of the project will have 3 separate study days (baseline, tadalafil, and placebo) and 2 medication visits (to receive the study medication and have their blood pressure checked by a study physician). Study days will be separated by at least two weeks to allow time for test results, to rest the forearm muscles between exercise bouts, and to ensure complete elimination of tadalafil. We plan to enroll 24 adult men with Becker muscular dystrophy, of whom 12 men will have dystrophin gene deletions between exons 41-46, and 24 healthy control subjects.