A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension

[1] *6 months to <18 years of age (at screening).;[2] Currently have a diagnosis of PAH that is either:;*idiopathic, including hereditary;;*related to connective tissue disease;;*related to anorexigen use;;*associated with surgical repair of at least 6-month duration of congenital systemic to pulmonary shunt (eg, atrial septal defect, ventricular septal defect, patent ductus arteriosus);[3] Have a history of a diagnosis of PAH established by a resting mean pulmonary artery pressure (mPAP) *25 mm Hg, pulmonary artery wedge pressure *15 mm Hg, and a PVR *3 Wood units via right heart catheterization (RHC). In the event that a pulmonary artery wedge pressure cannot be obtained during RHC, patients with a left ventricular end diastolic pressure (LVEDP)<15 mm Hg, with normal left heart function, and absence of mitral stenosis on echocardiography can be eligible for enrollment.;[4] Have a WHO functional class value of II or III at the time of screening.;[5] All subjects must be receiving an ERA (such as bosentan or ambrisentan) and must be on a maintenance dose with no change in dose (other than weight-based adjustments) for at least 12 weeks prior to screening and have a screening aspartate transaminase (AST)/alanine transaminase (ALT) <3 times the upper limit of normal (ULN).;[6] If on conventional PAH medication, including but not restricted to, anticoagulants, diuretics, digoxin, and oxygen therapy, the patient must be on stable doses with no changes (other than weight-based adjustments) for at least 4 weeks before screening. ;[7] Female patients of childbearing potential must test negative for pregnancy during screening. Furthermore, female patients must agree to abstain from sexual activity or to use two different reliable methods of birth control as determined by the Investigator during the study. Examples of reliable birth control methods include true abstinence as a lifestyle choice (periodic sexual abstinence method is not acceptable); the use of oral contraceptives; a reliable barrier method of birth control (diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices).;[8] Written informed consent from parents (and written assent from appropriately aged patients) will be obtained prior to any study procedure being performed.

[1] Pulmonary hypertension related to conditions other than specified in inclusion criteria.;[2] History of left-sided heart disease, including any of the following:;- clinically significant (pulmonary artery occlusion pressure [PAOP] 15 18 mm Hg) aortic or mitral valve disease (i.e., aortic stenosis, aortic insufficiency, mitral stenosis, moderate or greater mitral regurgitation);;- pericardial constriction;;- restrictive or congestive cardiomyopathy;;- left ventricular ejection fraction < 40% by multigated radionucleotide angiogram (MUGA), angiography, or echocardiography;;- left ventricular shortening fraction < 22% by echocardiography;;- life-threatening cardiac arrhythmias;;- symptomatic coronary artery disease within 5 years of study entry.;[3] History of atrial septostomy or Potts Shunt within 3 months before administration of study drug.;[4] Unrepaired congenital heart disease.;[5] History of angina pectoris or other condition that was treated with long- or short-acting nitrates within 12 weeks before administration of study drug.;[6] WHO functional class value of either I or IV at the time of screening.;[7] Severe hepatic impairment, Child-Pugh Grade C.;[8] Severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated creatinine clearance (CC) < 30 mL/min (Schwartz Formula);[9] Retinal disorder (e.g., hereditary retinal disorders, retinopathy of the preterm patient and other retinal disorders);[10] Severe hypotension or uncontrolled hypertension as determined by the Investigator.;[11] Significant parenchymal lung disease.;[12] Bronchopulmonary dysplasia.;[13] Concurrent PDE5 inhibitor therapy (sildenafil or vardenafil) or has received PDE5 inhibitor therapy within 24 hours prior to the first study drug dosing.;[14] Concurrent therapy with prostacyclin or its analogues.;[15] Previously completed or withdrawn from this study (LVHV), or any other study investigating tadalafil.;[16] Commenced or discontinued a chronic PAH medication including but not restricted to: calcium channel blockers, diuretics, anti-coagulants, digoxin, and oxygen therapy within four weeks of screening.;[17] Currently receiving treatment with doxazosin, nitrates, or cancer therapy.;[18] Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as rifampicin.;[19] History of loss of vision in 1 eye because of nonarteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous phosphodiesterase type 5 (PDE5) inhibitor exposure.;[20] Concurrent soluble guanylate cyclase stimulator therapy (such as riociguat) or has received soluble guanylate cyclase stimulator therapy within 12 weeks prior to first study drug dosing (Day 1, Visit 2)