Mono vs. Dual Therapy for Pediatric Pulmonary Arterial Hypertension

A Phase III, randomized, open label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in pediatric subjects with WHO Functional Classes II or III and precapillary pulmonary hypertension of Group 1 (PAH caused by idiopathic, heritable, drugs or toxins, congenital heart disease, or connective tissue disease) or Group 3 (PAH caused by lung disease or hypoxemia) according to the WHO (Nice) classification system. Precapillary pulmonary hypertension will be defined by standard criteria as mean pulmonary artery pressure over 25 mmHg and/or pulmonary vascular resistance index (PVRI) \> 3, as well as pulmonary capillary wedge pressure (or left ventricular end diastolic pressure) ≤ 15 mmHg as determined by cardiac catheterization. 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 (i-iv) are met: i. Two separate echocardiograms clearly demonstrate pulmonary hypertension by at least three of the following metrics 1. Elevated MPA pressure (early diastolic PR peak gradient \>20 mmHg) 2. Right ventricular hypertrophy (qualitative as mild to severe) 3. Right atrial enlargement (scales for age will be provided) 4. 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 5. Flattening or (R to L) bowing of the interventricular septum (qualitative or by elevated eccentricity index) 6. 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. Study subjects will be followed with current standard of care assessments and diagnostics, including longitudinal clinical evaluations, determinations of functional class (FC), serial NT-pro-Brain Natriuretic Peptide (NT-proBNP) levels, and echocardiography. Data from these studies will be analyzed in central core facilities that will be used by all participating study sites. Clinical endpoints are the focus of this study. However, additional data collection is planned for exploratory aims to examine the potential role for future application of novel metrics of outcomes in children with PAH (e.g., pediatric QOL and actigraphy), as described below. The investigators also plan to collect blood, swab and urine samples to determine whether inherent genomic variations or novel proteomic biomarkers will associate with clinical responsiveness to interventions within the cohort. Bio-specimens will be obtained to further test the hypothesis that therapeutic responders will have a different genomic or proteomic profile as compared to subjects who do not respond well to therapy. Bio-specimens will include the following: 1. Blood for DNA, peripheral blood mononuclear cells, plasma, and serum; and 2. Paired Box Gene (PAXgene) tubes for RNA and miRNA studies; and 3. Urine for biomarker analysis. Because sildenafil and bosentan have different mechanisms of action targeting different intracellular pathways, combination therapy is a rational treatment strategy for pediatric patients with PAH. Past work in adult PAH suggests that combination therapy with longer duration agents with the same mechanisms of action may cause greater and more sustained improvement in clinical course in comparison with monotherapy. Whether children with PAH respond and tolerate combination therapy better than monotherapy has not been studied. In addition, despite a growing experience with sequential therapy, additional medications are added only after clinical deterioration or failure to sustain responsiveness. Pharmacokinetics will be assessed during this study in order to determine whether drug levels or compliance with therapy affect outcomes in this cohort. In addition, pharmacokinetics data and related clinical responses from mono- and dual therapy participants will be compared. Interactions between these agents are well known, whereby bosentan decreases sildenafil levels. As a result, sildenafil levels during mono- and combination therapy will be further defined by the planned pharmacokinetics in the current protocol. In addition to strengthening this current study design, such data will form a basis for optimizing the use of these agents and potential strategies for dose adjustments in the broader scope of clinical care in the future.