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Phase II Trial of Sildenafil in Newborns with Persistent Pulmonary Hyptertension

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Persistent pulmonary hypertension of the newborn (PPHN) is associated with significant morbidity and mortality. Current management strategies include mechanical ventilation and inhaled nitric oxide therapy (iNO). iNO therapy has proven to be a safe and effective treatment for term newborns with PPHN, however, in randomized, controlled trials, approximately 40% of newborns still required treatment with extracorporeal membrane oxygenation (ECMO) because of the failure of INO therapy to cause sustained improvement in oxygenation. There are investigational adjuvant therapies that have the potential to cause selective pulmonary vasodilation and/or enhance the response to inhaled NO, such as the type 5 specific phosphodiesterase inhibitor sildenafil. Although enteral administration of sildenafil has been reported in newborns with PPHN, variable absorption in critically ill patients limits its application. We have recently completed a dose response/PK study using intravenous sildenafil (IVS) in infants with PPHN demonstrating that it is well tolerated and associated with marked improvements in oxygenation. We hypothesize that IVS will acutely reduce pulmonary artery pressure and improve oxygenation in near-term and term newborns with PPHN, thus reducing the need for rescue therapy with INO and/or ECMO. To test this hypothesis, we have designed a randomized, controlled, masked trial of IV sildenafil treatment In 50 near-term and term newborns with PPHN to be conducted at 5 clinical sites. This trial is designed to provide estimates for event rates (including mortality, ECMO utilization, and acute changes in pulmonary hypertension and gas exchange) that will guide power analysis for a larger, multicenter, randomized controlled trial of IVS in this population Specific Aim #1) To determine the acute changes in the physiological outcome measures of pulmonary artery pressure and gas exchange during treatment with IVS. Specific Aim#2: To determine the incidence of treatment failure (i.e. need for INO/ECMO) between the control and IVS treatment groups. In response to the RFA, the clinical trial will be augmented by 2 ancillary laboratory studies to be conducted at the University of Colorado and Northwestern University. RELEVANCE: In response to the RFA, we are proposing this phase II clinical therapeutic trial as a novel intervention for a severe lung disease affecting newborns. We are targeting physiological variables (as well as a treatment failure outcome measure) to generate event rates to provide proof of concept for this therapy that we believe has high potential for modifying current treatment strategies. (End of Abstract)

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