2/2 Kids MoD PAH Trial: Mono- vs. Duo-Therapy for Pediatric Pulmonary Arterial Hypertension-DCC

ABSTRACT
Pulmonary arterial hypertension (PAH) contributes to high morbidity and mortality in children with diverse
cardiopulmonary and systemic diseases. Efforts to define optimal treatment strategies for pediatric PAH have
been limited by the absence of multicenter randomized controlled trials (MRCTs) and the lack of well-defined and
proven endpoints for studies in children. Pediatric PAH remains understudied and relatively little is known about
long-term outcomes, age-appropriate clinical endpoints and optimal therapeutic strategies for children. Drug
treatment remains suboptimal as MRCTs are rare in children with PAH and current decision-making is dependent
on data from adult studies or small case series in children. Based on recent success of MRCTs in establishing a
new standard of care for adult PAH patients, we propose to study the potential role for initial up-front combination
treatment of PAH in children consisting of two PAH-specific oral therapies that have been shown to be well-
tolerated in children as monotherapies: sildenafil (a type V phosphodiesterase inhibitor) and bosentan (an
endothelin receptor antagonist). Recent studies in adult PAH suggest that initiation of combined therapy with a
phosphodiesterase 5 inhibitor and an endothelin receptor antagonist at the time of diagnosis, rather than
sequential combination therapy, improves pulmonary hemodynamics, exercise tolerance and quality of life when
compared with monotherapy. Children with PAH often require additional therapies over time in the setting of
disease progression or incomplete responsiveness to monotherapy, however, there are no data regarding the
potential benefits of greater and more sustained clinical improvement over time with the more aggressive
combination therapy approach from the time of initial diagnosis. Studies of pediatric PAH have been further
limited by the lack of well-coordinated and experienced care programs and the relative rare nature of these
diseases. With the collaboration of the Pediatric Pulmonary Hypertension Network (PPHNet), a highly interactive
and multidisciplinary group of academic PH programs, we propose to test the hypothesis that initiation of
up-front combination therapy with sildenafil and bosentan at the time of PAH diagnosis will result in
improved WHO Functional Class (FC) at 12 months in comparison with the current standard approach,
which is sildenafil therapy alone. Overall, this study addresses critical gaps in pediatric PAH by testing a clinical
strategy with strong potential for broad impact, and by defining useful study endpoints or novel surrogates that will
facilitate evidence-based decision-making and enhance the care of children with PAH.

Grant Number: 5U24HL151457-04
NIH Institute/Center: NIH
Principal Investigator: Hrishikesh Chakraborty