Becker Muscular Dystrophy Clinical Trial
Official title:
Functional Muscle Ischemia and PDE5A Inhibition in Becker Muscular Dystrophy
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.
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