Tadalafil in Becker Muscular Dystrophy
Condition: Becker Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Tadalafil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Tadalafil will be administered orally on two consecutive days. The first dose-10 mg- will be administered the afternoon before the study. The second dose -20 mg-will be administered the morning of the study.; A placebo pill will be administered orally on two consecutive days. The first pill will be administered the afternoon before the study. The second pill will be administered the morning of the study.
Other intervention name(s): Cialis
Intervention MeSH terms: Tadalafil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Muscular Dystrophy; Tadalafil