Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

A Phase 3, Multi-center, Open-label Study To Investigate Safety, Efficacy, And Tolerability Of Sildenafil Citrate In Pediatric Patients With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive, and life-threatening disease. In many patients, the course of PAH is a steady deterioration and reduced life expectancy.

Sildenafil was approved by the European Commission for the treatment of PAH in pediatric patients in May 2011, making it the first agent to be approved for the treatment of children with PAH. The approval was based on the largest placebo-controlled study to be conducted in this population. The recommended dose in pediatric patients aged 1 year to 17 years old is 10 mg TID in patients ≤ 20 kg and 20 mg TID for patients > 20 kg. Higher doses are not recommended in pediatrics patients.

This study is an open-label, multi-center study to investigate safety, efficacy and pharmacokinetics of sildenafil citrate in Japanese pediatric patients with PAH.

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 interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.