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

• ClinicalTrials.gov Identifier: NCT04447989
• Recruitment Status: Recruiting
• First Posted: June 25, 2020
• Last Update Posted: June 21, 2022
• Sponsor: Christoph P Hornik, MD MPH
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of North Carolina, Chapel Hill
• Information provided by (Responsible Party): Christoph P Hornik, MD MPH, Duke University

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Bronchopulmonary Dysplasia of Newborn	Drug: Sildenafil; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Premature infants with severe BPD (inpatient in neonatal intensive care units) will be randomized in a dose escalating approach 3:1 (sildenafil: placebo) sequentially, into each of 3 cohorts. There will be approximately 40 randomized and dosed participants in each cohort for a total of up to 120 participants.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Study drug (sildenafil or placebo) will be prepared in the pharmacy by the unblinded pharmacist. Treatment cohort will be randomly assigned electronically and communicated to the pharmacist via the study portal. All other study staff and the patients/parents will be blinded to the treatment assignment.
• Primary Purpose: Treatment
• Official Title: Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia
• Actual Study Start Date: May 27, 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

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 Name: Revatio
Placebo Comparator: Cohort 1, placebo; Placebo (IV or enteral) every 8 hours for 28 days	Drug: Placebo; dextrose 5%; Other Name: 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 Name: Revatio
Placebo Comparator: Cohort 2, placebo; Placebo (IV or enteral) every 8 hours for 28 days	Drug: Placebo; dextrose 5%; Other Name: 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 Name: Revatio
Placebo Comparator: Cohort 3, placebo; Placebo (IV or enteral) every 8 hours for 28 days	Drug: Placebo; dextrose 5%; Other Name: Dextrose 5%

Outcome Measures

Primary Outcome Measures :

1. Safety based upon incidence of hypotension [ Time Frame: Through 28 days post last dose of study drug ]

   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.

Secondary Outcome Measures :

1. Volume of Distribution [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
   Volume of distribution [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]
2. Clearance [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
   Clearance [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]
3. Half-life [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
   Half-life [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]
4. Area Under the Curve [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
   Area Under the Curve [ Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]
5. Peak Plasma Concentration [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
   Peak Plasma Concentration [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]

Other Outcome Measures:

1. Global rank [ Time Frame: Through study completion, 28 days after the last dose of study drug ]
   Clinically significant events ranked in order of decreasing perceived severity. Each participant will receive a rank based upon the lowest ranking (worst) endpoint as defined in the statistical analysis plan that they experienced during the study.

Eligibility Criteria

• Ages Eligible for Study: up to 29 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Project Leader; 919-668-8115; mary.bailey@duke.edu

Contact: Project Leader; 919-668-8282; Jacqueline.Huvane@duke.edu

Locations

United States, Arkansas

Arkansas Children's Research Institute; Recruiting

Little Rock, Arkansas, United States, 72202

Contact: Ankita Shukla, MD 501-364-7097 ashukla@uams.edu

United States, Florida

South Miami Hospital; Recruiting

Coral Gables, Florida, United States, 33146

Contact: Jorge Perez, MD 305-661-1515 jperezmd@kidzmedical.com

University of Florida Jacksonville Shands Medical Center; Active, not recruiting

Jacksonville, Florida, United States, 32209

United States, Georgia

Emory Children's Center; Recruiting

Atlanta, Georgia, United States, 30322

Contact: Shilpa Vyas-Read, MD 404-727-2401 svyasre@emory.edu

United States, Illinois

Lurie Children's Hospital; Recruiting

Chicago, Illinois, United States, 60611-2605

Contact: Megan Lagoski, MD 312-227-4190 mlagoski@luriechildrens.org

United States, Louisiana

Ochsner Baptist Medical Center; Recruiting

New Orleans, Louisiana, United States, 70115

Contact: Amanda England, MD 504-894-2619 amanda.england@ochsner.org

United States, Massachusetts

Boston Children's Hospital; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Kristen Leeman, MD 617-355-7909 kristen.leeman@childrens.harvard.edu

United States, New York

University of Rochester School of Medicine Children's Hospital; Recruiting

Rochester, New York, United States, 14642

Contact: Gloria Pryhuber, MD 585-507-8107 gloria_pryhuber@urmc.rochester.edu

United States, North Carolina

University of NC at Chapel Hill; Recruiting

Chapel Hill, North Carolina, United States, 27599

Contact: Jennifer Talbert 984-974-7865 jtalbert@med.unc.edu

Principal Investigator: Wesley Jackson, MD

East Carolina University; Recruiting

Greenville, North Carolina, United States, 27858

Contact: Ryan Moore, MD 252-744-4690 moorer15@ecu.edu

United States, Ohio

Rainbow Babies and Childrens Hospital; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Stephanie Ford, MD 216-844-3387 stephanie.ford@uhhospitals.org

Nationwide Children's Hospital; Recruiting

Columbus, Ohio, United States, 43205

Contact: Leif Nelin, MD 614-355-6719 leif.nelin@nationwidechildrens.org

United States, Tennessee

Vanderbilt Children's Hospital; Recruiting

Nashville, Tennessee, United States, 37232-9544

Contact: Joern-Hendrik Weitkamp, MD 615-322-3476 hendrik.weitkamp@vumc.org

United States, Virginia

University of Virginia Children's Hospital; Recruiting

Charlottesville, Virginia, United States, 22908

Contact: Michael McCulloch, MD 434-872-1143 mam3fk@virginia.edu

Sponsors and Collaborators

Christoph P Hornik, MD MPH

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

More Information

Publications of Results:

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.

Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, Laptook AR, Sánchez 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.

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001 Jun;163(7):1723-9.

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.

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. Review.

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.

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.

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. Review. Update in: Cochrane Database Syst Rev. 2017 Oct 24;10 :CD001146.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Christoph P Hornik, MD MPH, Associate Professor of Pediatrics, Duke University
• ClinicalTrials.gov Identifier: NCT04447989
• Other Study ID Numbers: Pro00104901; 1R61HL147833-01 ( U.S. NIH Grant/Contract )
• First Posted: June 25, 2020
• Last Update Posted: June 21, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is no plan to make IPD available to other researchers

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Bronchopulmonary Dysplasia; Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Sildenafil Citrate; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents