Hypoplastic Left Heart Syndrome, Tricuspid Atresia
Conditions
Keywords
Other Single Ventricle Anatomy, Hypoplastic Left Heart Syndrome, Tricuspid Atresia
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.
Interventions
DRUGSildenafil
One 20 mg capsule of sildenafil will be taken by mouth three times-a-day.
DRUGPlacebo
One placebo capsule will be taken by mouth three times-a-day.
Sponsors
The Mark H. and Blanche M. Harrington Foundation
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 40 Years
Healthy volunteers
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks | Baseline and 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks | Baseline and 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 | Baseline and 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 | Baseline and 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. |
Participant flow
Recruitment details
Of 125 eligible subjects contacted by the study team, 28 (22%) participated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Study Population Subjects who were randomized to receive either Sildenafil 20mg three times a day by mouth or Placebo three times a day by mouth. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (6 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Study Population |
|---|---|
| Age, Continuous | 14.9 Years STANDARD_DEVIATION 5.1 |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 28 | 10 / 27 |
| serious Total, serious adverse events | 1 / 28 | 0 / 27 |
Outcome results
Primary
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.
Time frame: Baseline and 6 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks | Oxygen Consumption at Baseline (mL/kg/min) | 30.5 mL/kg/min | Standard Deviation 6.9 |
| Sildenafil | Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks | Oxygen Consumption at 6 Weeks (mL/kg/min) | 31.3 mL/kg/min | Standard Deviation 7.1 |
| Placebo | Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks | Oxygen Consumption at Baseline (mL/kg/min) | 30.5 mL/kg/min | Standard Deviation 6.9 |
| Placebo | Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks | Oxygen Consumption at 6 Weeks (mL/kg/min) | 31.3 mL/kg/min | Standard Deviation 7.5 |
p-value: 0.73Regression, Linear
Secondary
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.
Time frame: Baseline and 6 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks | Heart rate at Baseline (bpm) | 163 bpm | Standard Deviation 20 |
| Sildenafil | Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks | Heart rate at 6 Weeks (bpm) | 163 bpm | Standard Deviation 14 |
| Placebo | Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks | Heart rate at Baseline (bpm) | 163 bpm | Standard Deviation 15 |
| Placebo | Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks | Heart rate at 6 Weeks (bpm) | 163 bpm | Standard Deviation 15 |
p-value: 0.37Regression, Linear
Secondary
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.
Time frame: Baseline and 6 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks | Minute Ventilation at Baseline (L/min) | 68.8 L/min | Standard Deviation 25 |
| Sildenafil | Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks | Minute Ventilation at 6 Weeks (L/min) | 67.2 L/min | Standard Deviation 23 |
| Placebo | Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks | Minute Ventilation at Baseline (L/min) | 68.1 L/min | Standard Deviation 27 |
| Placebo | Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks | Minute Ventilation at 6 Weeks (L/min) | 68.8 L/min | Standard Deviation 26 |
p-value: 0.04Regression, Linear
Secondary
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.
Time frame: Baseline and 6 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks | Mean Respiratory rate at Baseline (breaths/min) | 53.7 breaths/min | Standard Deviation 8.9 |
| Sildenafil | Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks | Mean Respiratory rate at 6 Weeks (breaths/min) | 51.0 breaths/min | Standard Deviation 9.4 |
| Placebo | Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks | Mean Respiratory rate at Baseline (breaths/min) | 53.0 breaths/min | Standard Deviation 7.5 |
| Placebo | Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks | Mean Respiratory rate at 6 Weeks (breaths/min) | 53.0 breaths/min | Standard Deviation 8.3 |
p-value: 0.05Regression, Linear