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

Duchenne Muscular Dystrophy Clinical Trial

— REVERSE-DBMD  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01168908
• Other study ID #: NA-00036602
• Status: Terminated
• Phase: Phase 2
• Start date: September 2010
• Est. completion date: January 2014

Study information

• Verified date: February 2019
• Source: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Becker Muscular Dystrophy
• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Sildenafil
20mg tablet three times daily

Locations

Country	Name	City	State
United States	Kennedy Krieger Institute, Johns Hopkins School of Medicine	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.	Johns Hopkins University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	6 months compared to baseline
Secondary	Change in Cardiac Systolic and Diastolic Function by CMR	Cardiac volumes and systolic ejection parameters will be measured.	6 months and 12 months
Secondary	Change in Cardiac Mass	Left ventricular (LV) mass will be measured by CMR .	6 months and 12 months
Secondary	Change in Forced Vital Capacity (FVC) by Pulmonary Function Testing	Skeletal muscle function of the diaphragm will be measured using FVC by pulmonary function testing.	6 months and 12 months
Secondary	Change in Skeletal Muscle Strength	Skeletal muscle strength will be assessed by pincher and grip dynamometry	6 months and 12 months
Secondary	Ejection Fraction	Left ventricular ejection fraction by cardiac MRI was measured	6 months