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

Publication ,  Journal Article
Schneider, S; Bailey, M; Spears, T; Esther, CR; Laughon, MM; Hornik, CP; Jackson, W
Published in: BMC Pediatr
December 14, 2020

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.gov NCT04447989 . Registered 25 June 2020.

Duke Scholars

Published In

BMC Pediatr

DOI

EISSN

1471-2431

Publication Date

December 14, 2020

Volume

20

Issue

1

Start / End Page

559

Location

England

Related Subject Headings

  • Sildenafil Citrate
  • Pediatrics
  • Infant, Premature, Diseases
  • Infant, Premature
  • Infant, Newborn
  • Infant, Low Birth Weight
  • Humans
  • Bronchopulmonary Dysplasia
  • 4204 Midwifery
  • 3213 Paediatrics
 

Citation

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Schneider, S., Bailey, M., Spears, T., Esther, C. R., Laughon, M. M., Hornik, C. P., & Jackson, W. (2020). Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study. BMC Pediatr, 20(1), 559. https://doi.org/10.1186/s12887-020-02453-7
Schneider, Simone, Mary Bailey, Tracy Spears, Charles R. Esther, Matthew M. Laughon, Christoph P. Hornik, and Wesley Jackson. “Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study.BMC Pediatr 20, no. 1 (December 14, 2020): 559. https://doi.org/10.1186/s12887-020-02453-7.
Journal cover image

Published In

BMC Pediatr

DOI

EISSN

1471-2431

Publication Date

December 14, 2020

Volume

20

Issue

1

Start / End Page

559

Location

England

Related Subject Headings

  • Sildenafil Citrate
  • Pediatrics
  • Infant, Premature, Diseases
  • Infant, Premature
  • Infant, Newborn
  • Infant, Low Birth Weight
  • Humans
  • Bronchopulmonary Dysplasia
  • 4204 Midwifery
  • 3213 Paediatrics