Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia

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Project Summary Premature infants with bronchopulmonary dysplasia (BPD) often die and survivors have life-long morbidities. BPD is the most common morbidity of prematurity, and affects ~17,000 infants per year in the US. Because the consequences of BPD are catastrophic, neonatologists frequently use drugs without proven efficacy in an attempt to prevent BPD. Sildenafil is a potent inhibitor of type 5 phosphodiesterase approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension in adults. Preclinical models demonstrate that sildenafil suppresses inflammatory mediators that contribute to lung injury (and BPD) and improve lung vascular development. In case reports in premature infants with BPD-associated pulmonary hypertension, sildenafil improves BPD severity by decreasing oxygen requirement and mean airway pressure. These findings suggest that sildenafil likely is an effective therapy to prevent BPD. We will perform a randomized, controlled, sequential dose escalating, double-masked phase II trial of 4 weeks of sildenafil in up to 120 premature infants at high risk for BPD at up to 30 clinical sites. We will increase dose after a safety review of each 40 participants. The long-term goal is to advance public health by developing therapeutics to prevent BPD in premature infants. The short-term goals are to 1) Determine the safety of sildenafil in premature infants at high risk for BPD; 2) Determine the change in risk of BPD in premature infants receiving sildenafil and 3) Determine the PK of sildenafil in premature infants at high risk for BPD. The proposal will be led by Dr. Laughon, a neonatologist with strong training in epidemiology and clinical pharmacology. Dr. Laughon has led multicenter clinical pharmacology trials in premature infants. The team assembled is uniquely qualified, and strengths include extensive clinical research experience; internationally recognized thought leadership in neonatal and pediatric cardiology quantitative methods; and a successful history of productive on time and on budget NIH projects. The research environment at UNC and the DCRI at Duke provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals. At the conclusion of this proposal, the research team will submit these data to the FDA and provide critical safety, preliminary effectiveness, and PK data for the pivotal phase III efficacy trial which, if successful, will provide evidence for the only therapeutic conducted under federal regulatory oversight to prevent BPD in premature infants.