Sildenafil After the Fontan Operation (SAFO)
Primary Purpose
Hypoplastic Left Heart Syndrome, Tricuspid Atresia
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Sildenafil
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hypoplastic Left Heart Syndrome focused on measuring Other Single Ventricle Anatomy, Hypoplastic Left Heart Syndrome, Tricuspid Atresia
Eligibility Criteria
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 Cytochrome P450 3A4 (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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Sildenafil, then Placebo
Placebo, then Sildenafil
Arm Description
Sildenafil will be given at a dose of 20 mg three times-a-day for six weeks followed by a six week washout period followed by placebo for an additional six weeks.
Placebo will be given for six weeks followed by a six week washout period followed by Sildenafil which will be given at a dose of 20 mg three times-a-day for six weeks
Outcomes
Primary Outcome Measures
Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks
Oxygen consumption measurements were taken at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Secondary Outcome Measures
Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks
Heart rate was measured at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks
Respiratory rate was measured at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks
Minute ventilation measurements were taken at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Full Information
NCT ID
NCT00507819
First Posted
July 25, 2007
Last Updated
May 4, 2015
Sponsor
Children's Hospital of Philadelphia
Collaborators
The Mark H. and Blanche M. Harrington Foundation
1. Study Identification
Unique Protocol Identification Number
NCT00507819
Brief Title
Sildenafil After the Fontan Operation
Acronym
SAFO
Official Title
The Sildenafil After Fontan Operation Study
Study Type
Interventional
2. Study Status
Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
April 2009 (Actual)
Study Completion Date
July 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital of Philadelphia
Collaborators
The Mark H. and Blanche M. Harrington Foundation
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
In this study, the investigators will evaluate the effect of sildenafil on exercise tolerance in patients with a single cardiac ventricle who have undergone the Fontan operation. The investigators will also evaluate echocardiographic measures of ventricular function and measure quality of life changes using two validated quality of life measures. The hypothesis is that sildenafil will result in increased exercise tolerance in patients who have had the Fontan operation as compared to placebo.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoplastic Left Heart Syndrome, Tricuspid Atresia
Keywords
Other Single Ventricle Anatomy, Hypoplastic Left Heart Syndrome, Tricuspid Atresia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sildenafil, then Placebo
Arm Type
Active Comparator
Arm Description
Sildenafil will be given at a dose of 20 mg three times-a-day for six weeks followed by a six week washout period followed by placebo for an additional six weeks.
Arm Title
Placebo, then Sildenafil
Arm Type
Active Comparator
Arm Description
Placebo will be given for six weeks followed by a six week washout period followed by Sildenafil which will be given at a dose of 20 mg three times-a-day for six weeks
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Other Intervention Name(s)
Revatio, Viagra
Intervention Description
One 20 mg capsule of sildenafil will be taken by mouth three times-a-day.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
One placebo capsule will be taken by mouth three times-a-day.
Primary Outcome Measure Information:
Title
Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks
Description
Oxygen consumption measurements were taken at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Time Frame
Baseline and 6 Weeks
Secondary Outcome Measure Information:
Title
Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks
Description
Heart rate was measured at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Time Frame
Baseline and 6 Weeks
Title
Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks
Description
Respiratory rate was measured at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Time Frame
Baseline and 6 Weeks
Title
Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks
Description
Minute ventilation measurements were taken at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.
Time Frame
Baseline and 6 Weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 Cytochrome P450 3A4 (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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jack Rychik, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
12. IPD Sharing Statement
Citations:
PubMed Identifier
21382896
Citation
Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM, Rychik J. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 2011 Mar 22;123(11):1185-93. doi: 10.1161/CIRCULATIONAHA.110.981746. Epub 2011 Mar 7.
Results Reference
derived
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Sildenafil After the Fontan Operation
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