Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia (SILDI-SAFE)

This is a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study of sildenafil in premature infants (inpatient in Neonatal Intensive Care Units (NICUs)) with severe bronchopulmonary dysplasia (BPD).

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia of Newborn
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

Detailed Description

Screening/Baseline

Research staff will document informed consent from the parent/guardian for all participants who satisfy eligibility criteria. The following information will be recorded in the case report form (eCRF) from the clinical medical record:

1. Participant demographics, including birth weight and gestational age at birth
2. Maternal race/ethnicity
3. Medical history
4. Physical examination, including actual weight
5. All mean arterial pressure (MAP) obtained in the 24 hours before the first dose
6. Concomitant medications (within 24 hours prior to start of study drug)
7. Respiratory assessment
8. Laboratory evaluations
9. Echocardiogram: If performed per local standard of care < 14 days prior to start of study drug, a study-specific echocardiogram need not be repeated. If not performed per local standard of care < 14 days prior to start of study drug, an echocardiogram will be required to confirm eligibility.
10. Cardiac catheterization reports, if performed per local standard of care < 14 days prior to start of study drug.
11. Adverse events following initial study-specific procedure

Treatment Period

The treatment period will include Days 1-28 or last day of study drug if early withdrawal of study drug. The following information will be collected and recorded while the participant is on study drug:

1. Actual weight on study Days 7 (± 1 day), 14 (± 1 day), 21 (± 1 day), and 28 (± 1 day) of study drug administration
2. Date, time, amount, and route of study drug dose
3. All concomitant medications

4. MAP

   A. All MAP values obtained 24 hours after the first dose of study drug regardless of administration route.

   B. MAP values will be obtained at a minimum at the following time points i. Prior to the first dose of study drug or dose escalation: 2 hours (± 5 minutes), 1 hour (± 5 minutes), and 15 minutes (± 5 minutes) ii. If administration route is IV:

   1. During and following the first dose of study drug or dose escalation: MAP at start of infusion, every 15 minutes (± 5 minutes) during infusion, at end of infusion (inclusive of flush) (± 5 minutes), at 15 and 30 minutes (± 5 minutes) after end of infusion, hourly (± 15 minutes) for 4 hours, and once in the remaining 2 hours prior to the next dose.
   2. For subsequent IV doses, the lowest valid MAP value should be recorded daily while on study drug.

   iii. If the administration route is enteral:

   1. During and following the first dose of study drug or dose escalation: MAP at start of enteral administration, then every 15 minutes (± 5 minutes) for 90 minutes (1.5 hours), then every 30 minutes (± 5 minutes) for 60 minutes (1 hour), then hourly (± 15 minutes) for 4 hours, then once in the remaining 2 hours prior to the next dose.
   2. For subsequent enteral doses, the lowest valid MAP value should be recorded daily while on study drug.
5. Respiratory assessment, weekly
6. Laboratory evaluations, at least every other week
7. Echocardiograms and cardiac catheterization reports, if performed per local standard of care
8. Pharmacokinetic (PK) sampling (after Day 7)
9. Adverse events

Weaning Period (Cohorts 2 and 3)

The weaning period will begin following Day 28 of study drug or, following the last day of study drug if participant was withdrawn from study drug prior to Day 28 and the dose escalated to ≥ 0.5 mg/kg IV or ≥ 1 mg/kg enteral.

The following information will be collected and recorded while the participant is weaning from study drug:

1. Date, time, amount and route of study drug dose
2. MAP (the lowest MAP value on last day of wean should be recorded).
3. Respiratory assessment on last day of wean
4. Echocardiogram and cardiac catheterization reports, if performed per local standard of care
5. Adverse events

Follow-up Period

The follow-up period will include Days 1-28 after the last study drug dose; last study drug dose may occur prior to Day 28 for those participants who withdraw from study drug early; on Day 28 for those participants who complete the full treatment period; or after last weaning dose for those participants who require weaning. The following information will be reported in electronic data capture system (EDC) at Day 1 (+ 2 days) and 14 (± 2days) of the follow-up period (or days closest to and after Day 1 and 14, if >1 assessment is available), except for MAP, adverse events (AEs), and serious adverse events (SAEs) (which will be reported from Days 1-28 post last study drug dose) and standard of care echocardiograms or cardiac catheterization reports:

1. Physical examination, including actual weight
2. MAP (the lowest valid MAP value on follow-up Day 1, 14, 21, and 28 should be recorded).
3. Respiratory assessment
4. Laboratory evaluations
5. Echocardiogram on follow-up Day 1 (+2 days). If performed per local standard of care, a study-specific echocardiogram need not be repeated. If not performed per local standard of care on Day 1 (+2 days) of the follow-up period, an echocardiogram will need to be performed.
6. Echocardiograms and cardiac catheterization reports, if performed per local standard of care (during follow-up Days 1-28)
7. Adverse events and SAEs (during follow-up Days 1-28)

Final Study Assessment

Final study assessment will occur at the time of discharge or transfer. The following information will be collected:

1. Physical examination, including actual weight
2. Respiratory assessment
3. Echocardiogram and cardiac catheterization reports, if performed per local standard of care on the day of discharge or transfer or up to 2 days prior.
4. Global rank
5. Discharge information A. Discharge or transfer B. Death C. Duration of hospitalization
6. Record if treatment for retinopathy of prematurity (ROP) was required

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Research Institute
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas Medical Sciences
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital and Health Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Childrens National Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Jacksonville Shands Medical Center
    • Jacksonville, Florida, United States, 32209
      • Wolfson Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60611-2605
      • Lurie Children's Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville School of Medicine
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • Ochsner Baptist Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Childrens Mercy Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Children's Hospital of Nevada at University Medical Center
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester School of Medicine Children's Hospital
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center - New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University Of NC At Chapel Hill
    • Greenville, North Carolina, United States, 27858
      • East Carolina University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee Health Science Center
  • Texas
    • Austin, Texas, United States, 78723
      • University of Texas Health
    • Houston, Texas, United States, 77054
      • Women's Hospital of Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Documented informed consent from parent or guardian, prior to study procedures
2. < 29 weeks gestational age at birth
3. 32-44 weeks postmenstrual age

4. Receiving respiratory support at enrollment:

   • If 32 0/7-35 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional)
   • If 36 0/7-44 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional) OR continuous positive airway pressure (CPAP)

Note:

• Criteria 3 and 4 define severe BPD for the purposes of this study

• CPAP is defined as any of the following:

  • Nasal cannula > 2 liters per minute (LPM)
  • Nasal continuous positive airway pressure (NCPAP)
  • Nasal intermittent positive pressure ventilation (NIPPV)
  • Noninvasive neurally adjusted ventilatory assist (NAVA)
  • Any other device designed to provide positive pressure through a nasal device (e.g., RAM cannula, etc.)

Exclusion Criteria:

1. Previous enrollment and dosing in this study, protocol number (NHLBI-2019-SIL), "Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia (BPD)"
2. Previous exposure to sildenafil within 7 days prior to randomization*
3. Previous exposure to vasopressors within 24 hours prior to randomization*
4. Previous exposure to inhaled nitric oxide within 24 hours prior to randomization*
5. Previous exposure to milrinone within 24 hours prior to randomization*
6. Evidence of pulmonary hypertension or moderate/large patent ductus arteriosus (PDA) on the most recent echocardiogram performed within 14 days prior to randomization
7. Known major congenital heart defect requiring medical or surgical intervention in the neonatal period
8. Known allergy to sildenafil
9. Known sickle cell disease
10. Aspartate aminotransferase (AST) > 225 U/L < 72 hours prior to randomization
11. Alanine aminotransferase (ALT) > 150 U/L < 72 hours prior to randomization

12. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study.

    • Participant will be reassessed prior to dosing to reconfirm eligibility criteria.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort 1, sildenafil; Sildenafil (0.5 mg/kg IV or 1 mg/kg enteral) every 8 hours for 28 days	Drug: Sildenafil; Sildenafil citrate injection or powder for suspension; Other Names: Revatio
Placebo Comparator: Cohort 1, placebo; Placebo (IV or enteral) every 8 hours for 28 days	Drug: Placebo; dextrose 5%; Other Names: Dextrose 5%
Active Comparator: Cohort 2, sildenafil; Sildenafil (1 mg/kg IV or 2 mg/kg enteral) every 8 hours for 28 days	Drug: Sildenafil; Sildenafil citrate injection or powder for suspension; Other Names: Revatio
Placebo Comparator: Cohort 2, placebo; Placebo (IV or enteral) every 8 hours for 28 days	Drug: Placebo; dextrose 5%; Other Names: Dextrose 5%
Active Comparator: Cohort 3, sildenafil; Sildenafil (2 mg/kg IV or 4 mg/kg enteral) every 8 hours for 28 days	Drug: Sildenafil; Sildenafil citrate injection or powder for suspension; Other Names: Revatio
Placebo Comparator: Cohort 3, placebo; Placebo (IV or enteral) every 8 hours for 28 days	Drug: Placebo; dextrose 5%; Other Names: Dextrose 5%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Based Upon Number of Participants With Hypotension	Safety as determined by incidence of hypotension experienced by the participants through 28 days post last dose of study drug. Hypotension will be defined as any clinically significant low blood pressure event deemed by the treating physician to require intervention with a fluid bolus or the initiation or escalation of inotropic, vasopressor, or systemic steroid therapy with the specific intent to raise blood pressure.	28 days post last dose of study drug, up to 9 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Central Volume of Distribution (Vc) Population Pharmacokinetics (popPK)	Following the completion of 7 days (168 hours) of study drug administration
Peripheral Volume of Distribution (Vp) Population Pharmacokinetics (popPK)	Following the completion of 7 days (168 hours) of study drug administration
Clearance Population Pharmacokinetics (popPK)	Following the completion of 7 days (168 hours) of study drug administration
Half-life Population Pharmacokinetics (popPK)	Following the completion of 7 days (168 hours) of study drug administration
Peak Plasma Concentration Population Pharmacokinetics (popPK)	Following the completion of 7 days (168 hours) of study drug administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants at Each Global Rank	Global rank is defined as clinically significant events ranked in order of decreasing perceived severity. Rank descriptions are presented from most to least severe.	28 days post last dose of study drug, up to 9 weeks

Collaborators and Investigators

• Sponsor: Christoph Hornik
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of North Carolina, Chapel Hill
• Investigators: Principal Investigator: Christoph Hornik, MD, Duke UMC; Principal Investigator: Matt Laughon, MD, UNC

Publications and helpful links

General Publications

• Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007 Dec;120(6):1260-9. doi: 10.1542/peds.2007-0971.
• Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001 Jun;163(7):1723-9. doi: 10.1164/ajrccm.163.7.2011060. No abstract available.
• Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065.
• Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, Laptook AR, Sanchez PJ, Van Meurs KP, Wyckoff M, Das A, Hale EC, Ball MB, Newman NS, Schibler K, Poindexter BB, Kennedy KA, Cotten CM, Watterberg KL, D'Angio CT, DeMauro SB, Truog WE, Devaskar U, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015 Sep 8;314(10):1039-51. doi: 10.1001/jama.2015.10244.
• Schneider S, Bailey M, Spears T, Esther CR Jr, Laughon MM, Hornik CP, Jackson W. 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. 2020 Dec 14;20(1):559. doi: 10.1186/s12887-020-02453-7.
• Gonzalez D, Laughon MM, Smith PB, Ge S, Ambalavanan N, Atz A, Sokol GM, Hornik CD, Stewart D, Mundakel G, Poindexter BB, Gaedigk R, Mills M, Cohen-Wolkowiez M, Martz K, Hornik CP; Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee. Population pharmacokinetics of sildenafil in extremely premature infants. Br J Clin Pharmacol. 2019 Dec;85(12):2824-2837. doi: 10.1111/bcp.14111. Epub 2019 Dec 15.
• Morrow CB, McGrath-Morrow SA, Collaco JM. Predictors of length of stay for initial hospitalization in infants with bronchopulmonary dysplasia. J Perinatol. 2018 Sep;38(9):1258-1265. doi: 10.1038/s41372-018-0142-7. Epub 2018 Jun 8.
• Jackson W, Hornik CP, Messina JA, Guglielmo K, Watwe A, Delancy G, Valdez A, MacArthur T, Peter-Wohl S, Smith PB, Tolia VN, Laughon MM. In-hospital outcomes of premature infants with severe bronchopulmonary dysplasia. J Perinatol. 2017 Jul;37(7):853-856. doi: 10.1038/jp.2017.49. Epub 2017 Apr 6.
• Poets CF, Lorenz L. Prevention of bronchopulmonary dysplasia in extremely low gestational age neonates: current evidence. Arch Dis Child Fetal Neonatal Ed. 2018 May;103(3):F285-F291. doi: 10.1136/archdischild-2017-314264. Epub 2018 Jan 23.
• Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999 Jun 24;340(25):1962-8. doi: 10.1056/NEJM199906243402505.
• Doyle LW, Ehrenkranz RA, Halliday HL. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2014 May 13;(5):CD001146. doi: 10.1002/14651858.CD001146.pub4.

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2021
• Primary Completion (Actual): December 12, 2024
• Study Completion (Actual): January 15, 2025

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: June 24, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): January 26, 2026
• Last Update Submitted That Met QC Criteria: January 7, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Bronchopulmonary Dysplasia; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; Purines; Sulfonamides; Sulfones; Piperazines; Sildenafil Citrate
• Other Study ID Numbers: Pro00104901; 1R61HL147833-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make IPD available to other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No