117 PHASE 1 STUDY OF RECOMBINANT HUMAN B-TYPE NATRIURETIC PEPTIDE FOR PERSISTENT PULMONARY HYPERTENSION.

Background Persistent pulmonary hypertension (PPHN) is a disease of (near-)term infants in which the pulmonary vascular resistance remains elevated in the neonatal period resulting in hypoxemia. B-type natriuretic peptide (BNP) is a peptide hormone secreted by the heart ventricles in response to stress. It aids in the regulation of systemic blood pressure. BNP levels are elevated in infants with PPHN. Recombinant human BNP (nesiritide, Natrecor [Scios, Inc]) is a safe and effective treatment for adults with congestive heart failure (CHF). The BNP receptor is a membrane-bound protein linked to a cGMP second messenger that can act in the same pathway as NO leading to smooth muscle relaxation. Objective To determine the safety of nesiritide for the treatment of PPHN and collect preliminary data for a possible multicenter, randomized, placebo-controlled trial of the drug for the treatment of PPHN. Design/Methods This is an open-label phase 1 trial. The study drug will be administered in doses ranging from 0.005 μg/kg/min to 0.02 μg/kg/min. Vital signs will be monitored according to a predetermined schedule. The drug will be given for 72 hours or until the patient no longer requires mechanical ventilation. Inclusion Criteria: (1) Newborn Infant, (2) PPHN diagnosed by the combination of hypoxemia and elevated pulmonary pressure estimated from echocardiography, (3) intubated and on conventional or high-frequency ventilation, (4) Oxygenation Index greater than or equal to 5, (5) BNP level over 550 pg/mL on DOL 1 or 300 pg/mL on subsequent days. Exclusion Criteria: (1) Suspected or confirmed genetic anomaly, (2) structural congenital heart disease, (3) structural pulmonary anomaly, (4) OI over 40, (5) patient already meets criteria for starting ECMO, (6) clinical evidence of dehydration, (7) hypotension unresponsive to medical management. Labs: BNP level prior to starting infusion and then with each echocardiogram. CBC and CMP prior to starting study drug and then each day for 5 days. Echocardiograms: 2-5 hours after reaching target dose, 24-48 hours and 5-7 days after starting the infusion. Each study participant will receive a neurobehavioral screening evaluation (NICU Network Neurobehavioral Scalses, NNNS) prior to discharge. Progress Two patients have qualified for the study. After 72 hours of infusion, no adverse events occurred. Conclusion At the conclusion of this study, we will determine the maximum tolerated dose of nesiritide for PPHN (assuming the dose is within the range of the study protocol). With that information, we expect to develop a multicenter RCT of the drug for the treatment of PPHN.