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Sildenafil After the Fontan Operation (SAFO)

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ClinicalTrials.gov Identifier: NCT00507819
Recruitment Status : Completed
First Posted : July 27, 2007
Results First Posted : May 5, 2015
Last Update Posted : May 5, 2015
Sponsor:
Collaborator:
The Mark H. and Blanche M. Harrington Foundation
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Tracking Information
First Submitted Date  ICMJE July 25, 2007
First Posted Date  ICMJE July 27, 2007
Results First Submitted Date  ICMJE February 9, 2011
Results First Posted Date  ICMJE May 5, 2015
Last Update Posted Date May 5, 2015
Study Start Date  ICMJE December 2007
Actual Primary Completion Date April 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2015)
Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 25, 2007)
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) ]
Change History Complete list of historical versions of study NCT00507819 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2015)
  • Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2007)
  • Oxygen pulse [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • Ventricular function [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • Atrioventricular valvar regurgitation [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • Myocardial performance index [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • E:E (passive ventricular inflow/diastolic myocardial velocity) [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • Fontan flow pattern [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • Mesenteric artery pulsatility index [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • PedsQL 4.0 - a generic quality of life assessment [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
  • PCQLI - a disease specific quality of life assessment [ Time Frame: 6 weeks for each arm of the study (12 weeks total) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sildenafil After the Fontan Operation
Official Title  ICMJE The Sildenafil After Fontan Operation Study
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypoplastic Left Heart Syndrome
  • Tricuspid Atresia
Intervention  ICMJE
  • Drug: Sildenafil
    One 20 mg capsule of sildenafil will be taken by mouth three times-a-day.
    Other Names:
    • Revatio
    • Viagra
  • Drug: Placebo
    One placebo capsule will be taken by mouth three times-a-day.
Study Arms  ICMJE
  • Active Comparator: Sildenafil, then Placebo
    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.
    Interventions:
    • Drug: Sildenafil
    • Drug: Placebo
  • Active Comparator: Placebo, then Sildenafil
    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
    Interventions:
    • Drug: Sildenafil
    • Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 4, 2015)
28
Original Estimated Enrollment  ICMJE
 (submitted: July 25, 2007)
34
Actual Study Completion Date  ICMJE July 2009
Actual Primary Completion Date April 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries United States
 
Administrative Information
NCT Number  ICMJE NCT00507819
Other Study ID Numbers  ICMJE IRB 2007-4-5034
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Hospital of Philadelphia
Study Sponsor  ICMJE Children's Hospital of Philadelphia
Collaborators  ICMJE The Mark H. and Blanche M. Harrington Foundation
Investigators  ICMJE
Principal Investigator: Jack Rychik, MD Children's Hospital of Philadelphia
PRS Account Children's Hospital of Philadelphia
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP