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

Participant Inclusion Criteria
To be eligible to participate in this study, an individual must meet all of the following 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:
o If 32 0/7–35 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional)
o If 36 0/7–44 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional) OR continuous positive airway pressure (CPAP)
Note:
o Criteria 3 and 4 define severe BPD for the purposes of this study
o 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.)

Participant Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this study:
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
Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia Version 3.0
NHLBI-2019-SIL 20 APRIL 2023
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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.