Abstract 13503: Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the FUTURE-4 Study

Background: Inhaled nitric oxide (iNO) is the mainstay of therapy for persistent pulmonary hypertension of the newborn (PPHN), but does not fully reverse PPHN in at least 30% of cases. Endothelin levels are elevated in PPHN, leading to consideration of endothelin receptor antagonists as adjunctive therapy. Methods: This was a Phase 3, multi-center, randomized, placebo controlled trial to evaluate the efficacy and safety of bosentan in neonates with PPHN. Eligible patients were ≤34 weeks gestation, < 7days of age, and with persistent respiratory failure (defined as oxygenation index (OI) ≤12) after at least 4 hours of iNO treatment. After 2:1 randomization, bosentan 2 mg/kg or matching placebo was given by nasogastric tube twice daily for at least 48 hours, and up to 1 day after iNO weaning. Results: During the 2-year study period, 21 eligible neonates from 9 centers received study drug (13 bosentan, 8 placebo). The groups had similar gestational age, weight, and sex distribution. The bosentan group had higher baseline OI values and rates of parenchymal lung disease than placebo (Table). On Day 1, bosentan concentrations were low and highly variable. Steady-state conditions comparable to those observed in adult PAH patients were achieved by Day 5. Bosentan was well tolerated, and did not adversely affect systemic blood pressure or hepatic transaminases. Adverse events of anemia and edema were more frequent in the bosentan group, but none led to treatment discontinuation. Treatment failure (need for ECMO) and time to weaning from iNO or mechanical ventilation were not different between groups. Cox Proportional Hazards analysis showed that higher baseline OI increased time to weaning from iNO (p=0.007). Conclusions: Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in PPHN. This may be related to delayed absorption of bosentan in young, critically ill neonates. Additionally, baseline OI strongly affects weaning time from iNO. ![][1] [1]: /embed/graphic-1.gif