Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study

Abstract

Background Pulmonary hypertension is a deadly complication of bronchopulmonary dysplasia, the most common pulmonary morbidity of prematurity. Despite these catastrophic consequences, no evidence-based therapies are available for the prevention of pulmonary hypertension in this population. Sildenafil is a potent pulmonary vasodilator approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults. Preclinical models suggest a beneficial effect of sildenafil on premature lungs through improved alveolarization and preserved vascular development. Sildenafil may therefore prevent the development of pulmonary hypertension associated with lung disease of prematurity by reducing pulmonary vascular remodeling and lowering pulmonary vascular resistance; however, clinical trial evidence is needed. The present study, supported by the National Institutes of Health’s National Heart Lung and Blood Institute, will generate safety, pharmacokinetics, and preliminary effectiveness data on sildenafil in a population of premature infants with severe bronchopulmonary dysplasia at risk for pulmonary hypertension. Methods We have designed a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety trial of sildenafil in premature infants with severe bronchopulmonary dysplasia. We will randomize 120 premature infants < 29 weeks gestational age with severe bronchopulmonary dysplasia at 32–40 weeks postmenstrual age in a dose-escalating approach 3:1 (sildenafil: placebo) sequentially into each of 3 cohorts at ~ 30 clinical sites. Participants will receive up to 34 days of study drug, followed by 28 days of safety monitoring. The primary outcome will be safety as determined by incidence of hypotension. Secondary outcomes will include pharmacokinetics and preliminary effectiveness of sildenafil based on presence or absence of pulmonary hypertension diagnosed by echocardiography at the end of treatment period. Discussion Sildenafil is a promising intervention to prevent the development of pulmonary hypertension in premature infants with bronchopulmonary dysplasia. Clinical trials of sildenafil specifically designed for premature infants are urgently needed. The current study will make substantial contributions to scientific knowledge of the safety of sildenafil in premature infants at risk for pulmonary hypertension. Results from the study will be used by investigators to inform the design of a pivotal efficacy trial. Trial registration ClinicalTrials.govNCT04447989. Registered 25 June 2020.

A multidisciplinary approach to severe bronchopulmonary dysplasia is associated with resolution of pulmonary hypertension

“…Although many reports have demonstrated sildenafil safety in neonates ( 18 , 33 ), we share concerns for unintended impacts of sildenafil on vascular development, such as those raised after sildenafil-exposed fetuses demonstrated increased risk of neonatal PH ( 34 ). We look forward to the results of a placebo-controlled clinical trial studying safety of sildenafil in BPD that is currently under way ( 35 ).…”

Intravenous sildenafil for treatment of early and late pulmonary hypertension in preterm infants

“…These studies overall report bene cial effects of sildena l on echocardiographic grading of BPD-PH and oxygenation indices. A prospective multicenter, randomized, placebo-controlled trial on preterm infants <29 weeks of GA at risk for PH is ongoing (SILDI-SAFE trial) [32]. Our study adds new insights on preterm and ELBW-infants with sildena l treatment for primary early-PH in the rst days of life, and with almost a third of the population classi ed as ELGANs and nearly half of the cohort classi ed as ELBW infants.…”

Outcomes of High-Dose Inhaled Nitric Oxide and Oxygen Administration for Severe Pulmonary Hypertension With Bronchopulmonary Dysplasia

“…There is low-quality evidence to support sildenafil use in preterm infants, especially in the case of severe BPD PH [ 3 ]. The ongoing randomized study conducted to clarify the effect of sildenafil effect on BPD PH is expected to provide valuable information on the effect of the drug on BPD PH [ 8 ].…”