Mono vs. Dual Therapy for Pediatric Pulmonary Arterial Hypertension

Inclusion Criteria

• Children who have not been treated with long-term targeted PAH drug therapy, which include calcium channel blockers (CCB); prostanoids, endothelin receptor antagonists (ERA) or PDE-5 inhibitors (PDE5i) (note that agents used for vasoreactivity testing during cardiac catheterization, or for acute periprocedural stabilization will be discontinued prior to study enrollment these include inhaled nitric oxide and/or prostacyclin analogs) a. Children who have been receiving subtherapeutic dosing of sildenafil (and no other standing therapy) for less than 2 weeks at the time of their referral for evaluation at a PH Center, may be included after a washout period of two days. Subtherapeutic is defined as dosage less than those shown in Section 6.1.2 sildenafil dosing chart. If, prior to the initial diagnostic cardiac catheterization, the independent clinical practitioner is planning to stop low dose sildenafil that is judged to not have therapeutic impact on hemodynamics by echocardiography, one may include this candidate for enrollment. These children will be followed closely during the washout period for clinical findings of cardiorespiratory changes, and with echocardiography and NT-proBNP measurements. Abnormal findings on these screening tests will prompt consideration of acute initiation of inhaled nitric oxide therapy. Therapy for pulmonary hypertension as determined by randomization for the study, may be started immediately after the two day washout period.

• Diagnosis of PAH by cardiology diagnostics

1. Diagnosis by cardiac catheterization with in the previous six months: PAH is defined as the presence of mean pulmonary artery pressure > 25mmHg, pulmonary capillary wedge pressure (or left atrial or left ventricular end diastolic pressure) ≤ 15 mmHg, and pulmonary vascular resistance index (PVRI) > 3 Woods Units

2. For infants less than one year of age for whom cardiac catheterization is not considered as part of the clinical team's recommended approach, enrollment will be possible without catheterization if the following four criteria are met:

i. Two separate echocardiograms clearly demonstrate pulmonary hypertension by at least three of the following metrics:

• Elevated MPA pressure (early diastolic PR peak gradient >20 mmHg)

• Right ventricular hypertrophy (qualitative as mild to severe)

• Right atrial enlargement (scales for age will be provided)

• Elevated right ventricular systolic pressure (>35mmHg) on at least two at least two reliable spectral Doppler envelopes during the echocardiogram and in the setting of normal for age documented systolic blood pressure at least two reliable spectral Doppler envelopes during the echocardiogram.

• Flattening or (R to L) bowing of the interventricular septum (qualitative or by elevated eccentricity index)

• Diminished RV function (RV fractional area change <35%) and/or TAPSE below published normal range for age and weight.

ii. There is no clinical or imaging evidence of left heart dysfunction; iii. Pulmonary venous stenosis and atresia are ruled out by CT angiography or MRI unless all four pulmonary veins are unequivocally normal on the two separate echocardiograms; iv. There is no evidence of hemodynamically significant left-to-right shunting across an unrestricted systemic to pulmonary shunt (this is unlikely to be a concern for PFO, small ASD, or restrictive PDA or VSD).

• Age ≥3 months to < 18 years (until just before the 18th birthday);

• WSPH groups 1 or 3 NOT due to unrepaired congenital heart disease (other than a patent foramen ovale), OR single ventricle, OR Eisenmenger's syndrome (PLEASE NOTE that only patients with Group 1.1, 1.2, 1.3, and 1.4.4 or Group 3 PAH will be included and this does not include those with much rarer presentations with connective tissue disease, HIV infection, portal hypertension, schistosomiasis, or persistent PAH of the newborn);

• Current WHO FC II or III.

Exclusion Criteria

• Inability or failure to provide informed consent;

• The presence of syncope, overt RV failure, cyanotic "spells" or systemic hypotension within 4 weeks of enrollment;

• Evidence of diffuse or focal pulmonary venous disease, left-sided heart functional disease;

• Known hypersensitivity to metabolites, or formulation components such as vehicle, preservatives or fillers that are contained in the investigational drugs;

• Pregnancy or breastfeeding;

• Documented history in the medical record of noncompliance with other medical regimens within one year of screening;

• Recent (within 1 year) history of alcohol or illicit drug abuse;

• Participation in any clinical study involving another investigational drug or device within 4 weeks;

• Comorbidities

a. Disorders treated with cyclosporine A or glyburide

b. Disorders treated with CYP3A Inhibitors and Beta Blockers

c. Congenital heart disease that was repaired within 6 months of enrollment;

i. A repaired patent ductus arteriosus within two months prior to enrollment does not constitute an exclusion.

ii. Anatomic issues with a measured Qp:Qs on cardiac catheterization of 1.3 or less are not considered hemodynamically significant and will therefore not be exclusions (i.e. patent foramen ovale, atrial septal defect, small muscular ventricular septal defect, and patent ductus arteriosus)

• Laboratory values of exclusion at the screening visit

1. serum ALT or AST lab value that is > 2xULN

2. serum bilirubin lab value that is > 1.5xULN

3. creatinine clearance < 30 mL/min;

• Inability to comply with all study procedures and availability for duration of study;

• Inability to take oral medications as prescribed;

• Inability to agree to lifestyle considerations throughout the study (please see section 5.3) and for four weeks thereafter.

• Children over 1 year of age with WSPH group 1 PAH attributed to IPAH or HPAH who are robustly responsive to acute vasodilator testing and who might benefit from a first line trial of oral CCB therapy as assessed by the treating physician and as described in PAH guidelines.