Revatio for Heart Disease in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

This clinical trial is focused on cardiovascular disease due to dystrophin deficiency.
Dystrophin is normally localized to the muscle cell membrane where it interacts with a
complex of proteins including neuronal nitric oxide synthase (nNOS). DMD gene mutations lead
to the loss of dystrophin and to mislocalization and reduced activity of nNOS, consequently
reducing cyclic guanosine monophosphate (cGMP) and the activity of its downstream effector,
protein kinase G. Our group and others have shown that inhibition of phosphodiesterase 5
(PDE5) leads to favorable cardiac remodeling and improved vascular tone in animal models of
heart failure.

This will be a phase 2, randomized, double-blind, placebo-controlled single center study for
6 months followed by open-label period of 6 months in which all enrolled subjects receive
Revatio (a PDE5 inhibitor). A single dose of Revatio (20 mg three times daily) will be tested
based on the safety and efficacy of that dose for treatment of pulmonary hypertension.

The primary endpoint will be the change in cardiac left ventricular end-systolic volume
(LVESV) as determined by cardiac MRI after 6 months of Revatio compared to baseline. A 10%
change in LVESV will be considered significant. This degree of improvement has generally been
observed in cardiac therapies that improve survival such as ACE inhibitors, beta blockers,
and cardiac resynchronization. The change from baseline in LVESV after 6 months of Revatio
will be compared to the change in LVESV over 6 months with placebo. The study will extend for
an additional 6 months of open-label Revatio to provide data on 6 months versus 12 months of
Revatio treatment. Additional secondary endpoints will include differences in systolic and
diastolic LV function by MRI, differences in LV mass and fibrosis by MRI, brachial
flow-mediated vasodilation (peripheral endothelial function), and targeted exploratory
assessment of differences in skeletal muscle function using forced vital capacity (FVC) and
pincher and grip testing. Safety will be assessed by differences in the frequency and grade
of adverse events

The study is taking place at the Kennedy Krieger Institute/Johns Hopkins Medical Institutions
in Baltimore, MD. The trial requires out-patient visits over a 12-month period. Travel funds,
through a grant from Ryan's Quest, are available.

Inclusion Criteria:

1. DBMD as determined by either a skeletal muscle biopsy demonstrating absence or lack of
dystrophin, and/or genetic testing showing a mutation in the dystrophin gene
predictive of DBMD, as well as a consistent physical examination

2. Male gender

3. Age greater than or equal to 18 years

4. Cardiac dysfunction with ejection fraction less than or equal to 50% as determined by
echocardiogram, cardiac MRI, or multi-gated acquisition (MUGA) scan

5. On a stable dose of ACE-inhibitor or angiotensin receptor blocker (ARB) for at least 3
months; beta-adrenergic receptor blockers and glucocorticosteroids are not required
but if used, a stable dose for at least 3 months is required.

6. Ability of the subject or legal guardian to provide informed consent

7. Ability to adhere with study follow-up

8. Willingness to abstain from food and alcohol for 8 hours prior to FMD

Exclusion Criteria:

1. Use of nitrates or alpha-adrenergic receptor blockers

2. Known intolerance or allergy to sildenafil, or a history of any severe allergic or
anaphylactic reactions

3. Any medical or psychosocial condition, which, in the view of the study investigator,
makes study participation inadvisable

4. Known hereditary retinal disorder such as retinitis pigmentosa

5. History of priapism or conditions that may predispose to priapism such as sickle cell
anemia, multiple myeloma, or leukemia

6. Bleeding disorders

7. Active tobacco use

8. Chronic atrial fibrillation or frequent arrhythmia that would result in an irregular
pulse

9. Factors that would preclude obtaining an MRI study - (e.g. implantable pacemaker or
cardioverter-defibrillator; body habitus cannot fit into scanner)

10. Systolic blood pressure (SBP) less than 85 mmHg at baseline evaluation

11. Chronic kidney disease stages 4 and 5: GFR< 30 mL/min/1.73 m2 as determined by serum
cystatin C level and the equation eGFRcys = 76.7 x (serum cystatin C-1.18)

12. Current use of sildenafil.