Safety, Pharmacokinetics (PK) and Hemodynamic Effects of Ambrisentan in Single Ventricle Pediatric Patients

A. Purpose of the Study The purpose of the study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ambrisentan in children with single ventricle heart defects that are undergoing Fontan (stage III) surgical palliation. This is a double blind, placebo controlled study. The primary objective of this Phase I/II study is to assess the plasma PK, safety and PD of oral ambrisentan in children with surgically palliated single ventricle heart defects. A secondary objective will be to assess whether ambrisentan improves post-operative outcomes including amount and duration of chest tube drainage and hospital length of stay.

B. Background and Significance Complex congenital heart defects associated with underdevelopment of a ventricle account for ~8% of congenital heart disease with a birth incidence of 4-8/10000 live births. These single ventricle lesions are associated with high morbidity and 5 year mortality rates that approach 50%. Staged surgical palliation directs returning venous blood flow directly into the lungs so that pulmonary blood flow occurs without the aid of a pumping chamber. The final stage of surgery (stage III - the Fontan procedure) incorporates inferior caval blood flow directly into the pulmonary arteries. Consequently pulmonary blood flow and cardiac output are directly related to pulmonary vascular resistance and ventricular function. The limitations of single ventricle surgical palliation often result in a prolonged post-operative course with pleural effusions a particular concern. There is also continued long term attrition. Elevated pulmonary vascular resistance and impaired systemic ventricular function are important risk factors for early and late failure of single ventricle palliation.

Ambrisentan is an endothelin receptor antagonist that improves pulmonary and possibly systemic endothelial function. Ambrisentan is approved for treatment of pulmonary arterial hypertension in adults and is used off-label for treatment of pulmonary hypertension in childen. Children with single ventricle heart defects demonstrate both pulmonary and systemic endothelial dysfunction and may benefit from treatment with this drug. However pharmacokinetics and hemodynamic efficacy of ambrisentan have not been studied in single ventricle patients. The most widely used alternative agent, sildenafil, was recently associated with increased mortality in children. There is now a Food and Drug Administration (FDA) safety warning against use of sildenafil in children. The investigators have previously demonstrated hemodynamic benefits with use of sildenafil in these patients but ambrisentan is a potentially safer agent. Therefore this study would fill an unmet need to guide dosing and evaluate efficacy of ambrisentan in this vulnerable population.

C. Design and Procedures

This is a single-center, randomized, blinded PK study of ambrisentan in children ages ≥ 24 months and ≤120 months with single ventricle anatomy. There will be up to 20 subjects enrolled; 16 will receive ambrisentan and 4 will receive placebo. A small placebo control group is warranted to ensure that any treatment effect is not a result of post-operative improvement. Patients will be enrolled at the time of their routinely scheduled Fontan surgery.