Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

Inclusion Criteria

• Subjects weighing ≥8 kg.
• Subjects who have symptomatic pulmonary arterial hypertension due to one of the following conditions:
• Idiopathic pulmonary arterial hypertension; or
• Heritable pulmonary arterial hypertension; or
• Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts. If the defect(s) is repaired, the subject's condition should be stabilized hemodynamically; or
• Pulmonary arterial hypertension associated with d-transposition of the great arteries repaired within the first 30 days of life; or
• Pulmonary arterial hypertension in subjects who have undergone surgical repair of other congenital heart lesions and the condition should be stabilized hemodynamically and do not have clinically significant residual left-sided heart disease.
• Subjects 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.

Exclusion Criteria

• Left-sided heart disease.
• Subjects with Down syndrome.
• Subjects with Obstructive Sleep Apnea, regardless of treatment status.
• Pericardial constriction.
• Subjects with significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation.
• Acutely decompensated heart failure within previous 30 days from screening.
• Subjects who have had an atrial septostomy within previous 6 months of screening.
• Subjects with hemodynamic instability or hypo- or hypertension at screening.
• Subjects with a history of stroke, myocardial infarction or life threatening arrhythmia within 6 months of screening.
• Subjects with 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.
• Subjects with history of pulmonary embolism.
• Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION).
• Subjects who are known to be HIV positive.
• Subjects with impairment of renal function (serum creatinine >2.5 × ULN) or hepatic function (ALT and/or AST >3 × ULN; and/or bilirubin ≥2 mg/dL). Hematological abnormalities (e.g., severe anemia, Hgb <10 g/dL, leukopenia, WBC <2500/µL).
• Subjects with severe hepatic dysfunction (Child-Pugh classification C).
• 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.
• Subjects taking chronic arginine supplementation.
• Subjects who have received parenteral inotropic medication or parenteral vasodilators within 30 days of Day 1.
• Subjects who are receiving alpha-blockers, nicorandil, amiodarone or potent cytochrome P450 3A4 inhibitors.
• Subjects receiving chronic treatment with off-label sildenafil within 30 days of Day 1 are excluded. Subjects receiving an endothelin antagonist，PED5 inhibitor or, prostacyclin/prostacyclin analogue within 30 days of randomization are excluded except for beraprost.
• Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 28 days after last dose of investigational product.
• 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.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may inte