Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial

Jason E Lang; Chi D Hornik; Karen Martz; Juliana Jacangelo; Ravinder Anand; Rachel Greenberg; Christoph Hornik; Kanecia Zimmerman; P Brian Smith; Daniel K Benjamin; Matthew Laughon; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee

doi:10.1016/j.conctc.2022.101025

Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial

Contemp Clin Trials Commun. 2022 Oct 31:30:101025. doi: 10.1016/j.conctc.2022.101025. eCollection 2022 Dec.

Authors

Jason E Lang^{1

2}, Chi D Hornik^{1

2}, Karen Martz³, Juliana Jacangelo³, Ravinder Anand³, Rachel Greenberg^{1

2}, Christoph Hornik^{1

2}, Kanecia Zimmerman^{1

2}, P Brian Smith^{1

2}, Daniel K Benjamin^{1

2}, Matthew Laughon⁴; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee

Affiliations

¹ Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
² Duke Clinical Research Institute, Durham, NC, USA.
³ The Emmes Company, LLC, Rockville, MD, USA.
⁴ Department of Pediatrics, The University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.

Abstract

Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to alveolar simplification, impaired alveolar-capillary development, interstitial fibrosis, and often pulmonary hypertension. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus is a promising candidate for BPD. Following phase I studies, we developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD. SIL02 is a randomized, double-blind, placebo-controlled, 3-cohort, sequential dose-escalating trial of enteral or intravenous (IV) sildenafil dosed every 8 h for up to 34 days. The target IV doses were 0.125, 0.5 and 1 mg/kg/dose in cohorts 1, 2 and 3, respectively; while the enteral doses will be double the IV doses. Eligible infants must be < 29 weeks' gestation at birth and requiring respiratory support at 7-28 days' postnatal age. Adverse events and preliminary effectiveness will be compared by treatment group. Using the final population PK model, empirical Bayesian estimates will be generated for each patient. Preliminary effectiveness will be measured by the incidence of moderate to severe BPD or death at 36 weeks and change in the BPD risk estimation.

Keywords: Bronchopulmonary dysplasia; Prematurity; Sildenafil.