Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia
Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia
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).
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 once a 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
Inclusion Criteria:

 1. Documented informed consent from parent or guardian, prior to study procedures

 2. < 29 weeks gestational age at birth

 3. 32-40 weeks postmenstrual age

 4. Receiving respiratory support at enrollment:

 -  If 32-36 weeks postmenstrual age: mechanical ventilation (high frequency or
 conventional)

 -  If > 36-40 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. Evidence of pulmonary hypertension or moderate/large patent ductus arteriosus (PDA) on
 the most recent echocardiogram performed within 14 days prior to randomization

 6. Known major congenital heart defect requiring medical or surgical intervention in the
 neonatal period

 7. Known allergy to sildenafil

 8. Known sickle cell disease

 9. Aspartate aminotransferase (AST) > 225 U/L < 72 hours prior to randomization

 10. Alanine aminotransferase (ALT) > 150 U/L < 72 hours prior to randomization

 11. 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.