Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia (SILDI-SAFE): A Randomized Controlled Trial.

Abstract

To describe the safety of sildenafil based on hypotension in premature infants with bronchopulmonary dysplasia (BPD). We conducted a multicenter, randomized, double-blind, placebo-controlled, dose-escalating trial of sildenafil. Infants born < 29 weeks' gestation and at 32-44 weeks postmenstrual age with severe BPD were randomized sequentially into 3 cohorts to receive up to 34 days of intravenous or enteral sildenafil citrate vs placebo (3:1) in a dose-escalating approach. Safety was determined by the incidence of hypotension through 28 days following the last dose of study drug. Pulmonary hypertension by serial echocardiography and daily respiratory severity scores were obtained to assess preliminary efficacy. A total of 122 infants received sildenafil (N = 92) or placebo (N = 30). The incidence of hypotension did not differ between the sildenafil (1/92) and placebo (0/30) groups. Serious adverse events occurred in 8% of the sildenafil group and 13% of the placebo group; retinopathy of prematurity requiring treatment in 17% and 30%, abnormal hearing results in 8% and 7%, direct hyperbilirubinemia in 4% and 3%, alanine aminotransferase elevation in 3% and 0%, and escalation in respiratory support in 7% and 20%, respectively. There were no differences in daily respiratory severity scores between groups. Among premature infants with severe BPD, enteral sildenafil citrate did not increase the incidence of hypotension or retinopathy of prematurity. Although we found possible differences between groups in the development of BPD-associated pulmonary hypertension diagnosed by echocardiography in high-risk infants, a larger, randomized controlled trial is needed to assess efficacy. ClinicalTrials.gov; Identifier: NCT04447989.