A Randomized, Double-Blind, Placebo-Controlled Study of Sildenafil in Children With Pulmonary Arterial Hypertension.
A Randomized, Double-Blind, Placebo-Controlled Study of Sildenafil in Children With Pulmonary Arterial Hypertension.
This is a clinical research study designed to evaluate sildenafil for the treatment of
 Pulmonary Arterial Hypertension in children, aged 1 to 17 years. The purpose of the study is
 to assess the efficacy, safety, and pharmacokinetics of 16 weeks of chronic treatment with
 oral sildenafil given in three different doses, compared to placebo (inactive treatment).
 Efficacy will be measured by exercise and hemodynamics. Patients who complete this trial may
 be eligible to take part in an extension study, in which all patients will receive active
 treatment of sildenafil.
Inclusion Criteria:

 -  Male or female subjects aged from 1 to 17 years old and weighing >= 8 kg with a mean
 pulmonary artery pressure >= 25 mmHg at rest, PCWP <= 15 mmHg, and PVRI >= 3 Wood
 units x m2 (if PCWP is not available, then mean LA pressure <= 15 mmHg or LVEDP <= 15
 mmHg in the absence of left atrial obstruction).

 -  Females of child bearing potential who were sexually active must have been practicing
 a suitable method of birth control so that in the opinion of the investigator, they
 would not become pregnant during the study.

 -  Subjects who have symptomatic pulmonary arterial hypertension due to: primary
 pulmonary hypertension; pulmonary arterial hypertension in the presence of a small or
 hemodynamically insignificant congenital systemic to pulmonary shunt lesion that in
 the opinion of the investigator is not the cause of pulmonary hypertension; collagen
 vascular disease; congenital systemic-to-pulmonary shunts with a baseline resting room
 air oxygen saturation >= 88% unrepaired or repaired at least 6 months prior to
 screening; d-transposition of the great arteries repaired within the first 30 days of
 life; or surgical repair of other congenital heart lesions at least 6 months prior to
 screening and do not have clinically significant residual left-sided heart disease
 consistent with the exclusion criteria.

 -  Subjects, developmentally able to exercise, whose CPX exercise test functional
 capacity is within the following parameters: Peak VO2 >= 10 mL/kg/min and <= 28
 mL/kg/min during screening CPX test;

 -  Written informed consent and assent where applicable before the subject is screened
 for the study.

 -  Subjects who undergo a large shift in altitude (defined as approximately 5000 feet or
 1524 meters) in order to participate in the study must reside at the "in study"
 altitude for at least 90 days prior to baseline and during the study period.

 Exclusion Criteria:

 -  Subjects with pulmonary hypertension secondary to sickle cell disease, any other
 disease known to be associated with PAH, or any etiology other than those specified in
 the inclusion criteria.

 -  Left-sided heart disease, including aortic or mitral valve disease (greater than
 mild), restrictive or congestive cardiomyopathy; PCWP or LVEDP > 15 mmHg; LVEF < 40%
 determined by MUGA, angiography or echocardiography; LV shortening fraction < 22%
 determined by echocardiography, symptomatic coronary disease (demonstrable ischemia).

 -  Pericardial constriction; significant (2+ for regurgitation) valvular disease other
 than tricuspid or pulmonary regurgitation; acutely decompensated heart failure within
 previous 30 days from screening; atrial septostomy within previous 6 months of
 screening;

 -  Hemodynamic instability or hypo- or hypertension at screening, i.e., SBP outside of
 70-140 mmHg.

 -  A history of stroke, myocardial infarction or life threatening arrhythmia within 6
 months of screening.

 -  Moderate to severe restrictive pulmonary disease (Total Lung Capacity or Forced Vital
 Capacity <= 60% of normal) or history of severe lung disease.

 -  Subjects with bronchopulmonary dysplasia (BPD) and other chronic lung diseases.

 -  History of pulmonary embolism.

 -  Subjects whose CPX test is limited by conditions other than pulmonary
 hypertension-associated dyspnea or fatigue.

 -  Subjects who are known to be HIV positive

 -  Subjects with impairment of renal function (serum creatinine > 2.5x ULN ) or hepatic
 function (ALT and/or AST > 3x ULN; and/or bilirubin >= 2 mg/dL). Hematological
 abnormalities (e.g., severe anemia, Hgb < 10 g/dL, leukopenia, WBC < 2500/mL).

 -  Subjects who previously received bosentan and whose liver function tests taken at
 screening are > 2x ULN.

 -  Subjects with any medical condition which in the opinion of the investigator may
 interfere with treatment, evaluation of safety, and/or efficacy.

 -  Change in class of medication for CHF or PAH within the 10 days prior to qualifying
 right heart catheterization.

 -  Subjects who are currently prescribed and/or taking nitrates or nitric oxide donors in
 any form. Acute vasodilator testing with nitric oxide is permitted during hemodynamic
 evaluation; taking chronic arginine supplementation including Heart Bar; therapy
 involving parenteral inotropic medication or parenteral vasodilators within 3 months
 of screening; current therapy with alpha-blockers, potent cytochrome P450 3A4
 inhibitors (e.g., erythromycin, ketoconazole, itraconazole and protease inhibitors),
 Ritonavir or Nicorandil; chronic treatment with off-label sildenafil, an endothelin
 antagonist or prostacyclin/prostacyclin analogue within 30 days of randomization.

 -  Pregnant or lactating female.

 -  Any medical or psychological condition or social circumstances that would impair their
 ability to participate reliably in the study or who were not likely to complete the
 study for any reason; current or past illicit drug use or alcoholism excepting if
 abstinence can be documented for >= 1 year.

 -  Participation in another clinical trial of an investigational drug or device
 (including placebo) within 30 days of screening for entry into the present study.

 -  Subjects with known hereditary degenerative retinal disorders (such as retinitis
 pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION).