Revatio for Heart Disease in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy (REVERSE-DBMD)

Phase 2 Clinical Trial of Sildenafil for Cardiac Dysfunction in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

This study, supported by Charley's Fund, Inc., is being done to determine if the drug Revatio®(also known as Sildenafil), as compared to placebo (an inactive substance that looks like the study drug, but contains no medication), improves heart function in people with Duchenne Muscular Dystrophy and Becker Muscular Dystrophy (DBMD). In people with DBMD, dystrophin is not present or lacking in heart and muscle. This is associated with abnormalities in an enzyme called "neuronal nitric oxide synthase" or nNOS, and leads to decreases in "cyclic GMP," which is necessary for proper function of those muscles. Revatio blocks an enzyme called phosphodiesterase 5 (PDE5), and helps to restore the normal amounts of cyclic GMP. The purpose of this research is to determine if Revatio is safe for people with DBMD and if it can improve heart function. Hypothesis : PDE5 inhibition, with the use of Revatio, will improve cardiac function in patients with DBMD.

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.

This arm will receive Revatio (sildenafil) for 12 months. During the first 6 months, the subject and investigator will be blinded to treatment. The second 6 months, will be open label treatment with Revatio.

This arm will receive placebo (sugar pill) for 6 months and Revatio (sildenafil) for 6 months. During the first 6 months, the subject and investigator will be blinded to treatment. The second 6 months, will be open label treatment with Revatio.

Change in Cardiac Left Ventricular End-systolic Volume (LVESV) by Cardiac Magnetic Resonance (CMR) Imaging.

To determine whether a 6 month trial of oral sildenafil compared to placebo improves cardiac contractile function in DBMD as determined by a > 10% decline in end-systolic volume as detected by CMR.

Inclusion Criteria: 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 Male gender Age greater than or equal to 18 years Cardiac dysfunction with ejection fraction less than or equal to 50% as determined by echocardiogram, cardiac MRI, or multi-gated acquisition (MUGA) scan 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. Ability of the subject or legal guardian to provide informed consent Ability to adhere with study follow-up Willingness to abstain from food and alcohol for 8 hours prior to FMD Exclusion Criteria: Use of nitrates or alpha-adrenergic receptor blockers Known intolerance or allergy to sildenafil, or a history of any severe allergic or anaphylactic reactions Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable Known hereditary retinal disorder such as retinitis pigmentosa History of priapism or conditions that may predispose to priapism such as sickle cell anemia, multiple myeloma, or leukemia Bleeding disorders Active tobacco use Chronic atrial fibrillation or frequent arrhythmia that would result in an irregular pulse Factors that would preclude obtaining an MRI study - (e.g. implantable pacemaker or cardioverter-defibrillator; body habitus cannot fit into scanner) Systolic blood pressure (SBP) less than 85 mmHg at baseline evaluation 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) Current use of sildenafil.

Leung DG, Herzka DA, Thompson WR, He B, Bibat G, Tennekoon G, Russell SD, Schuleri KH, Lardo AC, Kass DA, Thompson RE, Judge DP, Wagner KR. Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Ann Neurol. 2014 Oct;76(4):541-9. doi: 10.1002/ana.24214. Epub 2014 Jul 10.