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

• Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc. (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01168908
• Collaborator: Johns Hopkins University (Other)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 40
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy; Becker Muscular Dystrophy	Drug: Sildenafil	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Revatio
Other: 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 Names: Revatio

Outcome Measures

Primary Outcome Measures

1. Change in Cardiac Left Ventricular End-systolic Volume (LVESV) by Cardiac Magnetic Resonance (CMR) Imaging. [6 months compared to baseline]

   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

1. Change in Cardiac Systolic and Diastolic Function by CMR [6 months and 12 months]

   Cardiac volumes and systolic ejection parameters will be measured.

2. Change in Cardiac Mass [6 months and 12 months]

   Left ventricular (LV) mass will be measured by CMR .

3. Change in Forced Vital Capacity (FVC) by Pulmonary Function Testing [6 months and 12 months]

   Skeletal muscle function of the diaphragm will be measured using FVC by pulmonary function testing.

4. Change in Skeletal Muscle Strength [6 months and 12 months]

   Skeletal muscle strength will be assessed by pincher and grip dynamometry

5. Ejection Fraction [6 months]

   Left ventricular ejection fraction by cardiac MRI was measured

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None 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
• Other Study ID Numbers: NA-00036602
• First Posted: Jul 23, 2010
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Kathryn Wagner, Associate Professor of Neurology, Johns Hopkins University School of Medicine, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.: Clinical trial; Revatio; Sildenafil; Muscular Dystrophy; Duchenne; Becker; Adult; Adolescent
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Period Title: Double Blind, Placebo Controlled
STARTED	10	10
COMPLETED	7	8
NOT COMPLETED	3	2
Period Title: Double Blind, Placebo Controlled
STARTED	7	8
COMPLETED	6	7
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Revatio (Sildenafil)	Placebo	Total
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.5 (8.2)	22.6 (4.4)	24.05 (6.6)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	10 100%	10 100%	20 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 10%	2 20%	3 15%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 20%	0 0%	2 10%
White	7 70%	8 80%	15 75%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change in Cardiac Left Ventricular End-systolic Volume (LVESV) by Cardiac Magnetic Resonance (CMR) Imaging.
Description	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.
Time Frame	6 months compared to baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Measure Participants	7	8
Mean (Standard Deviation) [ml]	5.2 (23.61)	-0.19 (5.56)

2. Secondary Outcome

Title	Change in Cardiac Systolic and Diastolic Function by CMR
Description	Cardiac volumes and systolic ejection parameters will be measured.
Time Frame	6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Measure Participants	7	8
LV end-diastolic volume	5.54 (18.85)	0.24 (8.78)
stroke volume	0.34 (9.75)	0.43 (11.46)

3. Secondary Outcome

Title	Change in Cardiac Mass
Description	Left ventricular (LV) mass will be measured by CMR .
Time Frame	6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Measure Participants	7	8
Mean (Standard Deviation) [grams]	-3.4 (7.03)	-1.05 (12.69)

4. Secondary Outcome

Title	Change in Forced Vital Capacity (FVC) by Pulmonary Function Testing
Description	Skeletal muscle function of the diaphragm will be measured using FVC by pulmonary function testing.
Time Frame	6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Measure Participants	7	8
Mean (Standard Deviation) [liters]	-0.13 (0.09)	-0.19 (0.21)

5. Secondary Outcome

Title	Change in Skeletal Muscle Strength
Description	Skeletal muscle strength will be assessed by pincher and grip dynamometry
Time Frame	6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Measure Participants	7	8
pinch strength	-0.06 (0.30)	0.12 (0.45)
grip strength	0.37 (0.90)	0.17 (1.25)

6. Secondary Outcome

Title	Ejection Fraction
Description	Left ventricular ejection fraction by cardiac MRI was measured
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Revatio (Sildenafil)	Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily	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. Sildenafil: 20mg tablet three times daily
Measure Participants	7	8
Mean (Standard Deviation) [percentage of volume]	43.25 (12.82)	45.64 (6.82)

Adverse Events

Arm/Group Title	Revatio (Sildenafil)		Placebo
Arm/Group Description	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. Sildenafil: 20mg tablet three times daily		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. Sildenafil: 20mg tablet three times daily
All Cause Mortality
	Revatio (Sildenafil)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		0/10 (0%)
Serious Adverse Events
	Revatio (Sildenafil)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/18 (27.8%)		1/10 (10%)
Cardiac disorders
Death from heart failure	1/18 (5.6%)	1	0/10 (0%)	0
Gastrointestinal disorders
fecal impaction	0/18 (0%)	0	1/10 (10%)	1
Gastroparesis	1/18 (5.6%)	1	0/10 (0%)	0
Infections and infestations
Prostate infection	1/18 (5.6%)	1	0/10 (0%)	0
Metabolism and nutrition disorders
dehydration	1/18 (5.6%)	1	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
pneumonia	1/18 (5.6%)	1	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	Revatio (Sildenafil)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)		7/10 (70%)
Blood and lymphatic system disorders
Anemia	0/18 (0%)	0	1/10 (10%)	1
Cardiac disorders
tachycardia	1/18 (5.6%)	1	0/10 (0%)	0
low blood pressure	4/18 (22.2%)	4	0/10 (0%)	0
Gastrointestinal disorders
gastroparesis	1/18 (5.6%)	1	0/10 (0%)	0
gastroenteritis	2/18 (11.1%)	2	1/10 (10%)	1
Diarrhea	0/18 (0%)	0	2/10 (20%)	2
General disorders
Dizziness	1/18 (5.6%)	1	0/10 (0%)	0
flushing	1/18 (5.6%)	1	1/10 (10%)	1
tingling sensation	2/18 (11.1%)	2	0/10 (0%)	0
Nervous system disorders
Headache	1/18 (5.6%)	1	2/10 (20%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.