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).

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: Participant demographics, including birth weight and gestational age at birth Maternal race/ethnicity Medical history Physical examination, including actual weight All mean arterial pressure (MAP) obtained in the 24 hours before the first dose Concomitant medications (within 24 hours prior to start of study drug) Respiratory assessment Laboratory evaluations 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. Cardiac catheterization reports, if performed per local standard of care < 14 days prior to start of study drug. 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: Actual weight on study Days 7 (± 1 day), 14 (± 1 day), 21 (± 1 day), and 28 (± 1 day) of study drug administration Date, time, amount, and route of study drug dose All concomitant medications 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: 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. For subsequent IV doses, the lowest valid MAP value should be recorded daily while on study drug. iii. If the administration route is enteral: 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. For subsequent enteral doses, the lowest valid MAP value should be recorded daily while on study drug. Respiratory assessment, weekly Laboratory evaluations, at least every other week Echocardiograms and cardiac catheterization reports, if performed per local standard of care Pharmacokinetic (PK) sampling (after Day 7) 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: Date, time, amount and route of study drug dose MAP (the lowest MAP value on last day of wean should be recorded). Respiratory assessment on last day of wean Echocardiogram and cardiac catheterization reports, if performed per local standard of care 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: Physical examination, including actual weight MAP (the lowest valid MAP value on follow-up Day 1, 14, 21, and 28 should be recorded). Respiratory assessment Laboratory evaluations 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. Echocardiograms and cardiac catheterization reports, if performed per local standard of care (during follow-up Days 1-28) 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: Physical examination, including actual weight Respiratory assessment 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. Global rank Discharge information A. Discharge or transfer B. Death C. Duration of hospitalization Record if treatment for retinopathy of prematurity (ROP) was required

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.

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.

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.

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.

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.

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.

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.

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.

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.

Inclusion Criteria: Documented informed consent from parent or guardian, prior to study procedures < 29 weeks gestational age at birth 32-44 weeks postmenstrual age 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: Previous enrollment and dosing in this study, protocol number (NHLBI-2019-SIL), "Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia (BPD)" Previous exposure to sildenafil within 7 days prior to randomization* Previous exposure to vasopressors within 24 hours prior to randomization* Previous exposure to inhaled nitric oxide within 24 hours prior to randomization* Previous exposure to milrinone within 24 hours prior to randomization* Evidence of pulmonary hypertension or moderate/large patent ductus arteriosus (PDA) on the most recent echocardiogram performed within 14 days prior to randomization Known major congenital heart defect requiring medical or surgical intervention in the neonatal period Known allergy to sildenafil Known sickle cell disease Aspartate aminotransferase (AST) > 225 U/L < 72 hours prior to randomization Alanine aminotransferase (ALT) > 150 U/L < 72 hours prior to randomization 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.

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