Revatio for Heart Disease in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy (REVERSE-DBMD)
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.
Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Phase 2 Clinical Trial of Sildenafil for Cardiac Dysfunction in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy|
- Change in cardiac left ventricular end-systolic volume (LVESV) by cardiac magnetic resonance (CMR) imaging. [ Time Frame: 6 months and 12 months compared to baseline ] [ Designated as safety issue: No ]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.
- Change in cardiac systolic and diastolic function by CMR [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]Cardiac volumes, global and regional wall motion and ejection fraction, filling rates and regional strain rates, and systolic ejection parameters including maximal power and estimated end-systolic elastance, will be measured.
- Change in cardiac mass and remodeling by CMR [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]Left ventricular (LV) mass will be measured by CMR and cardiac fibrosis will be determined by delayed enhancement with gadolinium perfusion imaging.
- Change in arterial endothelial function by Flow Mediated Vasodilation (FMD) [ Time Frame: 6 months ] [ Designated as safety issue: No ]Brachial artery endothelial function will be measured by the change in arterial diameter before and after vaso-occlusion.
- Change in forced vital capacity (FVC) by pulmonary function testing [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]Skeletal muscle function of the diaphragm will be measured using FVC by pulmonary function testing.
- Change in self assessment of health and well-being [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]Self assessment of health and well-being will be determined through 2 questionnaires, a well validated general survey (SF-36) that is not disease specific and a newer survey (INQoL) that is specific to neuromuscular diseases.
- Change in skeletal muscle strength [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]Skeletal muscle strength will be assessed by pincher and grip dynamometry
|Study Start Date:||September 2010|
|Estimated Study Completion Date:||August 2014|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: Revatio (sildenafil)
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.
20mg tablet three times daily
Other Name: 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.
20mg tablet three times daily
Other Name: Revatio
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01168908
|United States, Maryland|
|Kennedy Krieger Institute, Johns Hopkins School of Medicine|
|Baltimore, Maryland, United States, 21205|
|Principal Investigator:||Daniel P Judge, MD||Johns Hopkins School of Medicine|
|Principal Investigator:||Kathryn R. Wagner, M.D., Ph.D.||The Kennedy Krieger Institute|