Official Title: “The Sildenafil After Fontan Operation Study”

In our study we will evaluate the effect of Sildenafil on exercise tolerance in patients with a single cardiac ventricle who have undergone the Fontan operation. We will also evaluate echocardiographic measures of ventricular function and measure quality of life changes using two validated quality of life measures. Our hypothesis is that Sildenafil will result in increased exercise tolerance in patients who have had the Fontan operation as compared to placebo.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment

Study Primary Completion Date: February 2008

The Fontan physiology is the end result of staged reconstruction of the heart and the major blood vessels in patients who have a single ventricle. After completion of the reconstruction, the great veins which usually bring blood back to the heart are connected directly to the pulmonary arteries, allowing blood from the body to bypass the heart and flow directly into the lungs. In this system, blood flow through the lungs is passive (not pumped) and the efficiency of flow through the cardiovascular system is related to the resistance to blood flow in the vessels of the lungs.

There are two potential problems that arise in this scenario, as a result of the resistance to blood flow in the vessels of the lungs. First, the amount of blood flow returning to the heart from the lungs may not be sufficient to allow the heart to function at maximum efficiency, compromising the heart's ability to keep up with the demands of the body.

Second, if the resistance to blood flow in the lungs is high, pressure may be transmitted back into the great veins themselves and secondarily into the organs of the body causing mild, or sometimes significant, organ dysfunction. Not all patients with the Fontan physiology develop these problems, but we know that even in patients without obvious problems, the ability to keep up with an increased metabolic demand, as during exercise, in compromised.

Improving the efficiency of blood flow through the lungs should improve the return of blood to the heart and thereby diminish the pressure transmitted back to the vessels which passively deliver blood to the lungs. We believe that this change may manifest as diminished symptoms in those patients with known difficulties, or may allow for an increased ability to walk, run, or participate in sports in those without any overt symptoms. Most importantly, we speculate that improved efficiency of flow through the lungs, and the resulting improved cardiac output (blood flow through the body) will make patients more energetic and will make them feel better.

Sildenafil is an oral medication that has been used to treat patients with pulmonary hypertension, a disease in which there is abnormally elevated pressure in the vessels of the lung. In this disease, the resistance in the lungs is abnormally high, severely limiting the ability of the heart to keep up with the demands of the body. Sildenafil lowers the resistance in the vessels of the lungs and has been shown to improve exercise performance in patients with this disease. We believe that Sildenafil may have a similar benefit for our patients after Fontan operation in whom cardiac output is also limited by resistance of the blood vessels in the lungs.

In our study, we will compare the exercise capacity, echocardiographic measures of cardiac function, and the overall quality of life in patients with the Fontan before and after a six-week period of Sildenafil administration. As a control, the same group of patients will take a placebo for a six-week period, also with before and after testing. We hypothesize that oral Sildenafil will result in significant improvements in exercise capacity, energy levels, and echocardiographic measures of cardiac function and output in our study participants. We are hopeful that the findings of this investigation will directly help children and young adults with Fontan physiology.

Intervention(s) in this Clinical Trial

• Drug: Sildenafil
  • One 20 mg capsule of sildenafil will be taken by mouth three times-a-day.
• Drug: Placebo
  • One placebo capsule will be taken by mouth three times-a-day.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Sildenafil will be given at a dose of 20 mg three times-a-day for six weeks.
• Placebo Comparator: 2
  • Placebo will be given three times-a-day for six weeks.

Primary Measures

• Change in maximal oxygen consumption from baseline testing to post-medication/placebo testing.
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No

Secondary Measures

• Oxygen pulse
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• Ventricular Function
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• Atrioventricular Valvar Regurgitation
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• Myocardial Performance Index
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• E:E' (passive ventricular inflow / diastolic myocardial velocity)
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• Fontan flow pattern
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• Mesenteric artery pulsatility index
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• PedsQL 4.0 - a generic quality of life assessment
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No
• PCQLI - A disease specific quality of life assessment
  • Time Frame: 6 weeks for each arm of the study (12 weeks total)
    Safety Issue?: No

Inclusion Criteria:

• 8 years of age or older
• All participants must have had Fontan completion

Exclusion Criteria:

• Height less than 132 cm
• Unable to participate in exercise testing due to medical restrictions or physical limitations.
• Fontan baffle obstruction or single lung physiology
• Coarctation of the aorta or neo-aorta (BP gradient > 20 mmHg)
• Severe ventricular dysfunction assessed qualitatively by echocardiography
• Severe atrioventricular valvar regurgitation assessed qualitatively by echocardiography
• Presence of electronic pacemaker
• History of treatment with Sildenafil in the six weeks prior to enrollment in study
• Patients with severe renal impairment
• Patients with severe hepatic impairment
• Patients taking medications that inhibit or induce CYP3A4 (including grapefruit juice and St. John's Wort)
• Patients taking alpha-blockers and nitrates
• Parents/Guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 8 Years

Maximum Age for this Clinical Trial: 40 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Hospital of Philadelphia

Overall Clinical Trial Officials and Contacts

Jack Rychik, MD Principal Investigator Children's Hospital of Philadelphia  

Overall Contact: Nicole Mirarchi  mirarchi@email.chop.edu

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00507819

Study ID Number: IRB 2007-4-5034

ClinicalTrials.gov Identifier: NCT00507819

Health Authority: United States: Food and Drug Administration