Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial
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 pul...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Contemporary Clinical Trials Communications |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2451865422001429 |
| _version_ | 1811295662145273856 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jason E. Lang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T05:36:41Z |
| format | Article |
| id | doaj.art-7620abb4d1534fd4ad1981a3fec1c5b2 |
| institution | Directory Open Access Journal |
| issn | 2451-8654 |
| language | English |
| last_indexed | 2024-04-13T05:36:41Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Contemporary Clinical Trials Communications |
| spelling | doaj.art-7620abb4d1534fd4ad1981a3fec1c5b22022-12-22T03:00:16ZengElsevierContemporary Clinical Trials Communications2451-86542022-12-0130101025Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trialJason E. Lang0Chi D. Hornik1Karen Martz2Juliana Jacangelo3Ravinder Anand4Rachel Greenberg5Christoph Hornik6Kanecia Zimmerman7P. Brian Smith8Daniel K. Benjamin9Matthew Laughon10Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA; Corresponding author.Duke Clinical Research Institute 300 W Morgan Street Durham, NC, 27701, USA.Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USAThe Emmes Company, LLC, Rockville, MD, USAThe Emmes Company, LLC, Rockville, MD, USAThe Emmes Company, LLC, Rockville, MD, USADepartment of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USADepartment of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USADepartment of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USADepartment of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USADepartment of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USADepartment of Pediatrics, The University of North Carolina-Chapel Hill, Chapel Hill, NC, USABronchopulmonary 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.http://www.sciencedirect.com/science/article/pii/S2451865422001429SildenafilBronchopulmonary dysplasiaPrematurity |
| spellingShingle | 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 Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial Contemporary Clinical Trials Communications Sildenafil Bronchopulmonary dysplasia Prematurity |
| title | Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial |
| title_full | Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial |
| title_fullStr | Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial |
| title_full_unstemmed | Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial |
| title_short | Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial |
| title_sort | safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia rationale and methods of a phase ii randomized trial |
| topic | Sildenafil Bronchopulmonary dysplasia Prematurity |
| url | http://www.sciencedirect.com/science/article/pii/S2451865422001429 |
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