Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia

Bronchopulmonary Dysplasia of Newborn Clinical Trial

— SILDI-SAFE  

Official title:

Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04447989
• Other study ID #: Pro00104901
• Secondary ID: 1R61HL147833-01
• Status: Recruiting
• Phase: Phase 2
• Start date: May 27, 2021
• Est. completion date: October 2024

Study information

• Verified date: June 2024
• Source: Duke University
• Contact: Project Leader
• Phone: 919-668-8115
• Email: mary.bailey[@]duke.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 29 Weeks

Eligibility

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.

Related Conditions & MeSH terms

• Bronchopulmonary Dysplasia
• Bronchopulmonary Dysplasia of Newborn

Intervention

Drug:
• Sildenafil
Sildenafil citrate injection or powder for suspension
• Placebo
dextrose 5%

Locations

Country	Name	City	State
United States	Emory Children's Center	Atlanta	Georgia
United States	University of Texas Health	Austin	Texas
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of NC at Chapel Hill	Chapel Hill	North Carolina
United States	Lurie Children's Hospital	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	East Carolina University	Greenville	North Carolina
United States	Women's Hospital of Texas	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Florida Jacksonville Shands Medical Center	Jacksonville	Florida
United States	Wolfson Children's Hospital	Jacksonville	Florida
United States	Childrens Mercy Hospital	Kansas City	Missouri
United States	Children's Hospital of Nevada at University Medical Center	Las Vegas	Nevada
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	Arkansas Children's Research Institute	Little Rock	Arkansas
United States	University of Arkansas Medical Sciences	Little Rock	Arkansas
United States	University of Louisville School of Medicine	Louisville	Kentucky
United States	University of Tennessee Health Science Center	Memphis	Tennessee
United States	Ochsner Baptist Medical Center	New Orleans	Louisiana
United States	University of Rochester School of Medicine Children's Hospital	Rochester	New York
United States	Rady Children's Hospital and Health Center	San Diego	California
United States	Westchester Medical Center - New York Medical College	Valhalla	New York
United States	Childrens National Medical Center	Washington	District of Columbia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Christoph Hornik	National Heart, Lung, and Blood Institute (NHLBI), University of North Carolina, Chapel Hill

Country where clinical trial is conducted

United States, 

References & Publications (10)

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. — View Citation

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 C — View Citation

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. — View Citation

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. — View Citation

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):12 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Global rank	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.	Through study completion, 28 days after the last dose of study drug
Primary	Safety based upon incidence of 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.	Through 28 days post last dose of study drug
Secondary	Volume of Distribution	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.]	Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration.
Secondary	Clearance	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.]	Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration.
Secondary	Half-life	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.]	Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration.
Secondary	Area Under the Curve	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.]	Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration.
Secondary	Peak Plasma Concentration	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.]	Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration.