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

This study has suspended participant recruitment.
(As recommended by the DSMB.)
Sponsor:
Collaborator:
Johns Hopkins University
Information provided by (Responsible Party):
Kathryn Wagner, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier:
NCT01168908
First received: July 22, 2010
Last updated: February 4, 2013
Last verified: February 2013
History of Changes
  Purpose

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.


Condition Intervention Phase
Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
 Drug: Sildenafil
 Phase 2

Study Type: Interventional
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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 30
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)
Arms Assigned Interventions
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.
 Drug: Sildenafil
20mg tablet three times daily
Other Name: Revatio
Placebo
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.
 Drug: Sildenafil
20mg tablet three times daily
Other Name: Revatio

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01168908

Locations
United States, Maryland
Kennedy Krieger Institute, Johns Hopkins School of Medicine
Baltimore, Maryland, United States, 21205
Sponsors and Collaborators
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Johns Hopkins University
Investigators
Principal Investigator: Daniel P Judge, MD Johns Hopkins School of Medicine
Principal Investigator: Kathryn R. Wagner, M.D., Ph.D. The Kennedy Krieger Institute
  More Information

No publications provided

Responsible Party: Kathryn Wagner, Associate Professor of Neurology, Johns Hopkins University School of Medicine, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier: NCT01168908     History of Changes
Other Study ID Numbers: NA-00036602
Study First Received: July 22, 2010
Last Updated: February 4, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:
Clinical trial
Revatio
Sildenafil
Muscular Dystrophy
 Duchenne
Becker
Adult
Adolescent

Additional relevant MeSH terms:
Muscular Dystrophy, Duchenne
Muscular Dystrophies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
 Sildenafil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2013