Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia
Phase: PHASE2
Conditions: Bronchopulmonary Dysplasia of Newborn
Sponsor: Christoph Hornik

Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia 
Version 2.2 
NHLBI-2019-SIL 
08 MARCH 2022 
 
 _____________________________________________________________________________________________ 
 
 
Safety of Sildenafil in Premature Infants with 
Severe Bronchopulmonary Dysplasia  
(SILDI-SAFE) 
Principal Investigator:  Christoph Hornik, MD, PhD, MPH 
Grantee Institution: Duke University 
Version Number:  2.2 
08 March 2022 
 
NCT04447989 
 

Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia 
Version 2.2 
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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Council for 
Harmonisation guidelines for Good Clinical Practice (GCP) (ICH E6) and the Code of 
Federal Regulations on the Protection of Human Subjects (45 CFR Part 46).The US 
Code of Federal Regulations (CFR) include but are not limited to:  
• 45 CFR 46 (Human Subjects Protection)  
• 45 CFR 160 and 164 Subparts A and E (Health Insurance Portability and 
Accountability Act [HIPAA] Privacy Rule) 
• 21 CFR 312 (Investigational New Drug [IND] Application) 
• 21 CFR 50 (Protection of Human Subjects, including Subpart D - Additional 
Safeguards for Children in Clinical Investigations)  
• 21 CFR 56 (Institutional Review Boards [IRB])  
National Institutes of Health (NIH)-funded investigators and all clinical trial site staff who 
are responsible for the conduct, management, or oversight of NIH-funded clinical trials 
have completed Human Subjects Protection, ICH GCP Training and are qualified to 
conduct this research.  

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PROTOCOL SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and 
provides the necessary assurances that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines.  
Clinical Site Investigator: 
Signed: _________  
 
 
 
Date:  
____ 
Name:  
Title:  

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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE .................................................................................... I 
PROTOCOL SIGNATURE PAGE .................................................................................. II 
TABLE OF CONTENTS ................................................................................................ III 
LIST OF TABLES.......................................................................................................... VI 
LIST OF ABBREVIATIONS .......................................................................................... VII 
PROTOCOL SUMMARY............................................................................................... IX 
1 
KEY ROLES AND CONTACT INFORMATION ...................................................... 1 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE .......................................................................................................... 1 
2.1 
Background Information ............................................................................ 1 
2.2 
Rationale .................................................................................................. 2 
2.3 
Potential Risks and Benefits ..................................................................... 7 
2.3.1 Potential Risks ............................................................................... 7 
2.3.2 Potential Benefits ........................................................................... 7 
3 
OBJECTIVES AND OUTCOME MEASURES ........................................................ 7 
3.1 
Objectives ................................................................................................. 7 
3.1.1 Primary Objective ........................................................................... 7 
3.1.2 Secondary Objectives .................................................................... 8 
3.1.3 Tertiary/Exploratory Objectives ...................................................... 8 
3.2 
Outcome Measures .................................................................................. 8 
3.2.1 Primary Outcome Measures ........................................................... 8 
3.2.2 Secondary Outcome Measures ...................................................... 8 
3.3 
Tertiary/Exploratory .................................................................................. 9 
3.3.1 Other Safety and Efficacy Outcomes.............................................. 9 
4 
STUDY DESIGN .................................................................................................... 9 
4.1 
Screening/Baseline ................................................................................... 9 
4.2 
Treatment Period ...................................................................................... 9 
4.3 
Weaning Period (Cohorts 2 and 3) .......................................................... 10 
4.4 
Follow-up Period ..................................................................................... 11 
4.5 
Final Study Assessment ......................................................................... 11 
5 
STUDY POPULATION ......................................................................................... 12 
5.1 
Participant Inclusion Criteria ................................................................... 12 
5.2 
Participant Exclusion Criteria .................................................................. 12 
5.3 
Strategies for Recruitment and Retention ............................................... 13 
5.4 
Treatment Assignment Procedures ......................................................... 13 
5.4.1 Randomization Procedures .......................................................... 13 
5.4.2 Masking Procedures – Enteral Dosing ......................................... 14 
5.5 
Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention .......................................................................... 14 
5.5.1 Reasons for Participant Withdrawal or Discontinuation from 
Study Procedures/Intervention ..................................................... 14 

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5.5.2 Handling of Participant Withdrawals from Study or Participant 
Discontinuation of Study Intervention ........................................... 15 
5.6 
Premature Termination or Suspension of Study ...................................... 16 
6 
STUDY INTERVENTION ..................................................................................... 16 
6.1 
Study Product Description ...................................................................... 16 
6.1.1 Study Placebos ............................................................................ 18 
6.1.2 Acquisition.................................................................................... 18 
6.1.3 Formulation, Packaging, and Labeling ......................................... 18 
6.1.4 Product Storage and Stability ....................................................... 19 
6.2 
Dosage, Preparation and Administration of Study Product...................... 19 
6.3 
Modification of Study Product Administration for a Participant ................ 19 
6.4 
Accountability Procedures for the Study Product .................................... 19 
6.5 
Concomitant Medications/Treatments ..................................................... 20 
6.5.1 Concomitant Medications of Special Interest ................................ 20 
7 
STUDY SCHEDULE ............................................................................................ 21 
7.1 
Table 6 Schedule of Study Procedures ................................................... 21 
8 
STUDY PROCEDURES/EVALUATIONS ............................................................. 22 
8.1 
Study Procedures/Evaluations ................................................................ 22 
8.2 
Laboratory Procedures/Evaluations ........................................................ 22 
8.2.1 Clinical Laboratory Evaluations .................................................... 22 
8.2.2 Special Assays or Procedures...................................................... 23 
8.2.3 Specimen Preparation, Handling, and Storage ............................. 24 
8.2.4 Specimen Shipment ..................................................................... 24 
9 
ASSESSMENT OF SAFETY ................................................................................ 24 
9.1 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters ............................................................................................. 24 
9.2 
Specification of Safety Parameters ......................................................... 25 
9.2.1 Unanticipated Problems ............................................................... 25 
9.2.2 Serious Adverse Events ............................................................... 25 
9.2.3 Serious Adverse Event Reporting Timelines ................................ 26 
9.2.4 Events of Special Interest ............................................................. 27 
9.2.5 Respiratory Support Escalation .................................................... 27 
9.2.6 Time Period and Frequency for Event Assessment and Follow-
Up 
27 
9.3 
Characteristics of an Adverse Event ....................................................... 28 
9.3.1 Relationship to Study Intervention ................................................ 28 
9.3.2 Severity of Event .......................................................................... 28 
9.4 
Adverse Event Reporting Procedures ..................................................... 29 
9.4.1 Expectedness .............................................................................. 29 
9.4.2 Reporting of Safety Events to FDA ............................................... 29 
9.4.3 Reporting of Hypotension ............................................................. 30 
9.4.4 Reporting of Pregnancy................................................................ 30 
9.5 
Halting Rules .......................................................................................... 30 
9.5.1 Discontinuation of a Participant Due to Adverse Events ............... 30 
9.5.2 Unscheduled DSMB Review and Study Discontinuation .............. 30 

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10 
STUDY OVERSIGHT ........................................................................................... 30 
11 
CLINICAL SITE MONITORING ............................................................................ 31 
12 
STATISTICAL CONSIDERATIONS ..................................................................... 31 
12.1 
Study Endpoints ..................................................................................... 31 
12.2 
Sample Size Considerations ................................................................... 31 
12.3 
Planned Interim Analyses ....................................................................... 32 
12.3.1 Safety Review .............................................................................. 32 
12.4 
Final Analysis Plan ................................................................................. 32 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ...... 34 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 34 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................ 35 
15.1 
Institutional Review Board ...................................................................... 35 
15.2 
Informed Consent Process ..................................................................... 35 
15.3 
Exclusion of Women, Minorities, and Children (Special Populations) ...... 36 
15.4 
Subject Confidentiality ............................................................................ 36 
15.5 
Future Use of Stored Specimens and Other Identifiable Data ................. 37 
16 
DATA HANDLING AND RECORD KEEPING ...................................................... 38 
16.1 
Data Management Responsibilities ......................................................... 38 
16.2 
Data Capture Methods ............................................................................ 38 
16.3 
Types of Data ......................................................................................... 38 
16.4 
Schedule and Content of Reports ........................................................... 38 
16.5 
Study Records Retention ........................................................................ 39 
16.6 
Protocol Deviations ................................................................................. 39 
17 
PUBLICATION/DATA SHARING ......................................................................... 39 
18 
LITERATURE REFERENCES ............................................................................. 41 

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LIST OF TABLES 
Table 1 
Simulated Median Steady-State Area under the Concentration vs. Time 
Profile 0- 24 Hours ......................................................................................................... 5 
Table 2 
Summary of All Adverse Events in Phase 1 Study of Sildenafil ................. 6 
Table 3 
Number of Participants (N) and Dosing Scheme ..................................... 16 
Table 4 
Dose Escalations for Each Sequential Cohort......................................... 17 
Table 5 
Weaning Schedule for Study Sildenafil or Placebo in Cohorts 2 and 3 ... 18 
Table 6 
Schedule of Study Procedures................................................................ 21 
Table 7 
Target PK Sampling Times ..................................................................... 23 
Table 8 
Widths for 95% Wilson Confidence Intervals........................................... 31 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BPD 
Bronchopulmonary Dysplasia 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CPAP 
Continuous Positive Airway Pressure 
eCRF 
Electronic Case Report Form 
DCC 
Data Coordinating Center 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data Safety Monitoring Board 
DMS 
N-desmethylsildenafil 
EDC 
Electronic Data Capture System 
ESI 
Events of Special Interest 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IV 
Intravenous 
LAR 
Legally Authorized Representatives 
LPM 
Liters per Minute 
MAP 
Mean Arterial Pressure 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NAVA 
Neurally Adjusted Ventilatory Assist  
NCPAP 
Nasal Continuous Positive Airway Pressure 
NHLBI 
National Heart Lung and Blood Institute 
NICHD 
National Institute of Child Health and Human Development 

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NICU 
Neonatal Intensive Care Unit 
NIH 
National Institutes of Health 
NIPPV 
Nasal Intermittent Positive Pressure Ventilation 
PAH 
Pulmonary Arterial Hypertension 
PH 
Pulmonary Hypertension 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PMA 
Postmenstrual Age (gestational age plus postnatal age) 
PP 
Per Protocol 
PTN 
Pediatric Trials Network 
q 
Every 
ROP 
Retinopathy of Prematurity 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAR 
Suspected Adverse Reaction 
U/L 
Units per Liter 
US 
United States 

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PROTOCOL SUMMARY 
Title: 
Safety of Sildenafil in Premature Infants with Severe 
Bronchopulmonary Dysplasia 
Précis: 
This is a multicenter, randomized, placebo-controlled, sequential 
dose-escalating, double-masked, safety study of sildenafil in 
premature infants with severe bronchopulmonary dysplasia (BPD). 
 
Number of Participants (N) and Dosing Scheme 
Cohort1 
Treatment Group 
Sildenafil 
Dosing2 
(mg/kg q 8 hours) 
Total (N) 
Placebo (N) 
Sildenafil (N) 
IV 
Enteral 
1 
10 
30 
0.5 
1 
40 
2 
10 
30 
1 
2 
40 
3 
10 
30 
2 
4 
40 
Abbreviations: IV, intravenous; N, number of participants; q, every 
1 Participants will be enrolled into cohorts sequentially (i.e., Cohort 1 then Cohort 
2 then Cohort 3) based on safety. 
2 Route of administration should be via IV route if patient has an IV and IV 
administration is feasible. However, route of administration, IV or enteral, is left to 
investigator discretion. 
Objectives: 
Primary: Describe the safety of sildenafil as determined by incidence 
of hypotension in premature infants with severe BPD. 
Secondary: Pharmacokinetics (PK) and preliminary effectiveness of 
sildenafil for the prevention of pulmonary hypertension in premature 
infants with severe BPD. 

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Population: 
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. 
 
For the purposes of this study, severe BPD is defined as:  
• 
32-44 weeks postmenstrual age at enrollment; and 
• 
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: Exclusion from participation due to enrollment in other clinical 
trials, including IND trials, will be left to the judgement of the site 
principal investigator (PI). Investigator judgement should consider the 
safety of the participant. 
Phase or 
Stage: 
2 
Number of 
Sites: 
Approximately 30 sites  
Description of 
Intervention: 
Sildenafil citrate injection and powder for suspension 
Study 
Duration: 
Approximately 36 months enrollment period with an additional 24 
months of data analyses (60 months total) 
Subject 
Participation 
Duration: 
Up to 62 days (up to 34 days of study drug plus 28 days of safety 
monitoring). Information about hospitalization will be collected at 
36 weeks postmenstrual age and/or at discharge. 
 

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1 KEY ROLES AND CONTACT INFORMATION 
Coordinating Center 
Principal Investigator and 
IND Sponsor: 
Christoph P. Hornik, MD, PhD, MPH 
Associate Professor of Pediatrics 
Duke University 
Duke Clinical Research Institute 
300 W. Morgan St. 
Durham, NC 27715 
Telephone: 919-668-8935 
Christoph.hornik@duke.edu 
Co-Principal Investigator: 
Matthew M. Laughon, MD, MPH 
Professor of Pediatrics 
The University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7596 
Telephone: 984-974-7851 
Fax: 984-974-7857 
Mobile: 919-824-6373 
Matt_laughon@med.unc.edu 
Medical Monitor and 
Protocol Chair: 
Wesley M. Jackson, MD, MPH 
Assistant Professor of Pediatrics 
The University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7596 
Telephone: 984-215-3449 
Fax: 984-974-7857 
Mobile: 817-343-6962 
Wesley.jackson@unc.edu 
NIH Program Official: 
Aruna Natarajan, MD, PhD 
Program Director 
National Institute of Health, National Heart, Lung, and 
Blood Institute 
Bethesda, MD 20892 
Telephone: 301-435-0222 
Aruna.natarajan@nih.gov 
2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
Sildenafil is approved by the FDA for the treatment of pulmonary arterial hypertension in 
adults to improve exercise ability and delay clinical worsening.1 The FDA does not 
recommend using sildenafil for pulmonary hypertension in children 1 to 17 years of age. 
Recommendations about sildenafil use in neonates and infants do not exist. Differences 

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in the cardiopulmonary pathophysiology targeted to neonates and infants suggest that 
sildenafil may be beneficial in this population. As a result, pharmacokinetic (PK) and 
safety studies of sildenafil in neonates and infants have been or are currently being 
conducted under the Best Pharmaceuticals in Children’s Act by the National Institute of 
Child Health and Human Development (NICHD)-funded Pediatric Trials Network (PTN).2 
The present study, supported by the National Heart Lung and Blood Institute (NHLBI), 
will generate additional safety, PK, and preliminary effectiveness data on sildenafil in a 
subpopulation of infants with severe bronchopulmonary dysplasia (BPD). 
2.2 
Rationale 
Over 50,000 infants are born < 29 weeks gestational age each year in the US, of whom 
nearly 40% develop BPD.3 BPD is defined by the NIH as either mild, moderate, or 
severe based on the respiratory support required at 36 weeks postmenstrual age.4 
Premature infants with severe BPD are particularly challenging and suffer from multiple 
morbidities including pulmonary hypertension (PH), prolonged hospitalization, death, 
and life-long morbidities.5–7 Because of the prevalence and seriousness of the disease, 
neonatologists are dedicated to preventing BPD.8 Vitamin A, caffeine, and postnatal 
steroids have all been shown to prevent BPD.9–11 Members of this protocol team (Drs. 
Hornik, Laughon, and Jackson) are currently performing trials to prevent BPD using 
sildenafil (NCT03142568). However, once BPD has developed, there are no drugs to 
prevent its associated morbidities including PH. This study seeks to address this 
knowledge gap by evaluating the safety, PK, and preliminary effectiveness of sildenafil 
in this population and was designed based on the rationale outlined below. 
Pulmonary hypertension is a deadly complication of severe BPD. Approximately 
20% of premature infants with severe BPD develop PH, and up to 40% of premature 
infants with severe BPD and PH die, usually due to right heart failure.5,12,13 In addition to 
higher mortality, infants with combined BPD and PH have longer hospitalizations and 
are more likely to require in-home respiratory support.14,15 The temporal relationship 
between BPD and PH in premature infants is complex. Early PH without concurrent 
BPD can be present in the first week of life in infants at the highest risk of BPD, such as 
those with fetal growth restriction.12 Only one-third of these infants will develop BPD 
later in life. In contrast, most infants with BPD who develop PH do so later in life: one 
prospective study of extremely low-birth-weight infants found that 65% of infants with 
BPD-related PH had normal echocardiograms at 4-6 weeks.16 BPD-related PH occurs 
due to impaired lung development resulting in decreased pulmonary vessel branching 
and vascular remodeling (Figure 1).17 Knowledge of this pathology and the delay in 
development of this severe complication offer an opportunity for prevention to decrease 
infant mortality. 

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Figure 1 Pathophysiology of pulmonary hypertension in infants with BPD 
 
Abbreviations: BPD, bronchopulmonary dysplasia; PH, pulmonary hypertension 
 
Sildenafil reduces lung injury and preserves normal vasculature in preclinical 
BPD models. BPD and PH are characterized by lung injury, inflammation, abnormal 
alveolarization, and dysregulated vascular development. Preclinical models 
demonstrate that sildenafil might prevent ischemic-perfusion injury and improve lung 
function (rat18), suppress inflammatory mediators (mouse19; rat20,21; also matrix 
metalloproteinase-2 in cell cultures22) that contribute to lung injury and BPD, and 
improve alveolarization and lung vascular development. Sildenafil is a potent inhibitor of 
phosphodiesterase type 5, the predominant isoform in the lung, which metabolizes 
cyclic guanosine monophosphate and produces pulmonary vasodilation. Sildenafil may 
thus prevent the development of BPD-related PH in premature infants by reducing 
pulmonary vascular remodeling and lowering pulmonary vascular resistance, but clinical 
trial evidence is needed. 
Sildenafil improves short-term outcomes in children and adults with pulmonary 
hypertension. Sildenafil is a potent inhibitor of type 5 phosphodiesterase, the 

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predominant isoform in the lung. Type 5 phosphodiesterase metabolizes cyclic 
guanosine monophosphate and produces pulmonary vasodilation. In adults, sildenafil is 
approved by the FDA for the treatment of pulmonary arterial hypertension.1 Children 
with pulmonary arterial hypertension (either idiopathic or due to preexisting cardiac 
disease) treated with sildenafil had improved aerobic capacity after 16 weeks of 
treatment, and the effect appeared to be dose dependent.23,24 In this study, children with 
BPD were excluded, and all participants were > 8 kg. Long-term follow-up demonstrated 
an increased risk of mortality in the highest sildenafil dosing group, (dosing was 
weight-based with the highest dose group receiving 20 mg thrice daily if weight was 
8-20 kg, 40 mg thrice daily if weight was 21-45 kg and 80 mg thrice daily if weight was 
> 45 kg).25 FDA does not recommend sildenafil use, particularly chronic use, in children 
and Health Canada states sildenafil is not indicated in pediatric patients.1,26  
Neonatologists frequently use sildenafil to treat infants with pulmonary 
hypertension. Two case reports documented the successful resolution of PH, 
measured by echocardiogram, in premature infants treated with sildenafil.27,28 In a small 
case series, enteral sildenafil at a dose range of 1.5-8 mg/kg/day in 25 premature 
infants with a median gestational age of 28 weeks (range 23-41 weeks) with lung 
disease (72% with BPD) resulted in improved hemodynamics by echocardiogram.29 A 
retrospective case series of 23 preterm infants with median gestational age of 26 weeks 
treated with 1-7.3 mg/kg/day of oral sildenafil found a substantial improvement in BPD 
related PH based on echocardiography in 71% of patients for whom echocardiographic 
data were complete (15/21).30 These data confirm that neonatologists usually treat PH 
in infants with BPD and are likely unwilling to randomize to placebo; thus, a prevention 
approach is needed. 
Neonatologists are using sildenafil without safety data. Neonatologists are 
increasingly using sildenafil in premature infants despite a lack of sufficient safety data, 
including data related to hypotension and retinopathy of prematurity (ROP). Despite 
neonatal medicine’s long history of catastrophic adverse events (AEs) resulting from 
inadequate study of drugs prior to their widespread use,31–34 the majority of drugs used 
in premature infants, including sildenafil, have undergone insufficient study to receive 
FDA labeling for this population.35–39 Extrapolating drug safety and dosing from adults 
underestimates the complicated physiology of premature infants, who have (1) larger 
extracellular fluid volume per unit body weight, (2) immature renal and hepatic function, 
and (3) disease-related changes in metabolizing organ function, each of which can alter 
drug disposition.40,41 Improper use of drugs in these vulnerable patients leads to 
increased treatment failure, AEs, mortality, and long-term morbidities.42 Sildenafil 
studies specifically designed for premature infants with BPD are urgently needed. 
These studies should initially focus on characterizing PK and safety in infants to inform 
the design of a pivotal efficacy trial. 
Sildenafil is increasingly used off-label in premature infants with BPD: A review of 
data from the Mednax Clinical Data Warehouse, a real-world data source representing 
approximately 20% of US Neonatal Intensive Care Unit (NICU) admissions,43 found an 

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exponential increase in sildenafil use by > 1000%, second highest of all drugs from 
2005 to 2010.44 Of the infants exposed to sildenafil, 79% had BPD and 84% had PH. 
A phase 1 opportunistic pilot study of sildenafil in premature infants under IND 
(NCT01670136) has been completed. Conducted under IND by the PTN, the trial 
enrolled 34 infants ≤ 28 weeks gestational age with a median birth weight of 666 g 
receiving intravenous (IV) or enteral sildenafil per standard of care at doses between 
0.13 mg/kg - 2.1 mg/kg. Pharmacokinetic and safety analyses were performed and are 
summarized below. 
The infant population PK model identified safe sildenafil starting doses for early phase 
trials. Using 109 plasma samples collected in 34 infants in a multicenter phase 1 
open-label PK study of sildenafil in premature infants, we developed a 2-compartment 
population PK model of sildenafil and its primary active metabolite N-desmethylsildenafil 
(DMS). Population estimates of parent sildenafil elimination clearance and central 
volume of distribution were 27.8 L/h/70kg and 116 L/70kg; relative DMS elimination 
clearance and volume of distribution, were 135 L/h/70kg and 1670 L/70kg.2 The model 
simulated sildenafil a DMS exposures at different enteral and IV dosing regimens to 
identify safe doses for evaluation in a dose escalation trial (Table 1). Starting doses of 
0.5 mg/kg IV (or 1 mg/kg enteral) resulted in combined AUC0-24,SIL+DMS comparable to a 
previously reported value of 2650 ng*hr/mL which has been associated with infant 
survival.45 However, exposure targets for PH prevention in infants with severe BPD are 
unknown and will be further elucidated in this trial. 
Table 1 Simulated Median Steady-State Area under the Concentration vs. Time 
Profile 0- 24 Hours 
Intravenous Dosing (every 8 hours) 
0.5 mg/kg 
1 mg/kg 
Sildenafil (ng*hr/ml) 
3157 
6314 
DMS (ng*hr/ml) 
669 
1337 
Sildenafil + 62.5%DMS (ng*hr/ml) 
3581 
7163 
Enteral Dosing (every 8 hours) 
1 mg/kg 
2 mg/kg 
Sildenafil (ng*hr/ml) 
1825 
3650 
DMS (ng*hr/ml) 
1608 
3217 
Sildenafil + 62.5%DMS (ng*hr/ml) 
2941 
5883 
Abbreviation: DMS, N-desmethylsildenafil 
 
The safety analysis identified overall incidence and events of special interest: The 
safety analysis included all 34 infants. There were 23 adverse events in 15 participants 
and 5 serious adverse events (SAEs) in 5 participants, including 1 episode of 
hypotension, the only event related to sildenafil, in an infant receiving IV sildenafil 
(Table 2). This event was determined to be related to a faster than expected infusion 
rate of IV sildenafil. The event led to a data monitoring committee (DSMB) review of 
available data, and a review of all clinical sites’ infusion methods and equipment. The 
protocol was changed prior to enrolling the remaining Cohort 2 subjects to include a 

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longer infusion time (30 minutes) and the dose was lowered by 50% to 0.125 mg/kg. 
When the study reopened, 2 additional subjects were enrolled without any related AEs. 
Table 2 Summary of All Adverse Events in Phase 1 Study of Sildenafil 
 
Cohort 1  
(N = 25) 
Cohort 2  
(N = 9) 
Number of Events/Participants 
 
 
Number of AEs 
13 
10 
Participants with at least one AE 
8 (32.0%) 
7 (77.8%) 
Number of SAEs 
1 
4 
Participants with at least one SAE 
1 (4.0%) 
4 (44.4%) 
Severity (All AEs) 
 
 
Mild 
7 
3 
Moderate 
4 
3 
Severe 
2 
4 
Highest Severity per Participant 
 
 
Mild 
4 (16.0%) 
2 (22.2%) 
Moderate 
3 (12.0%) 
1 (11.1%) 
Severe 
1 (4.0%) 
4 (44.4%) 
Relationship (All AEs) 
 
 
Not related 
13 
9 
Related 
0 
1 
Strongest Relationship per Participant 
 
 
Not related 
8 (32.0%) 
6 (66.7%) 
Related 
0 
1 (11.1%) 
Abbreviations: AE, adverse event; N, number of participants; SAE, serious adverse event 
 
Echocardiography is a reliable surrogate endpoint for the diagnosis of pulmonary 
hypertension in premature infants: With support from NHLBI (R34HL14038), 
members of the current study team (Drs. Hornik and Laughon) assigned 3 blinded 
pediatric cardiologists to review 483 echocardiograms from 49 infants < 29 weeks 
gestational age at birth (range 22–28) admitted to the neonatal intensive care units of 
UNC or Duke. PH diagnosis was a priori defined using tricuspid regurgitation jet and, if 
unavailable, a composite score of echocardiographic measures. The proposed score 
had high inter (modified Fleiss Kappa 0.759 (0.771, 0.801) and intra-rater reliability 
(Fleiss Kappa 0.847 (0.75, 0.931), and acceptable internal consistency (Cronbach’s 
alpha 0.64)46. Importantly, the score identified infants with PH with a prevalence (33%) 
and mortality (34%) comparable to prior reports. Mortality was significantly lower (10%) 
for infants not diagnosed with PH. 
Based on the above data, sildenafil is a promising potential intervention to prevent the 
development of PH in premature infants with BPD. Prior to the completion of definitive 
efficacy trials, an evaluation of its safety, PK, and preliminary effectiveness are 
essential. 

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2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
2.3.1.1 
Risks of Blood Sampling 
There are small risks to blood sampling including minor pain or discomfort with the 
needle stick and blood loss. Every effort will be made to avoid needle sticks in excess of 
standard of care for this study and every effort will be made to time clinical blood draws 
to coincide with timed samples, using existing IV lines when possible. 
2.3.1.2 
Sildenafil 
There are several risks associated with administering sildenafil in premature infants, 
including: 
1. A theoretical increased risk of ROP associated with sildenafil  has been 
suggested in a case report in the literature;47 however, case-control and cohort 
studies have not found a significant association between sildenafil exposure and 
ROP.48–50 
2. Sildenafil has vasodilatory properties that can result in mild and transient 
decreases in blood pressure. See sildenafil package insert for additional 
information.1 
Adverse events were previously observed in the phase 1 opportunistic pilot study of 
sildenafil in premature infants (NICHD-2012-SIL0; see Table 2, Section 2.2). Safety 
data will also be reviewed prior to dose escalation between cohorts. Risks of ROP have 
been minimized by administering sildenafil during the time when screening for ROP 
begins (31-32 weeks adjusted age). Treatment of ROP is an exploratory outcome 
(Section 3.3.1). 
2.3.2 Potential Benefits 
Sildenafil may improve pulmonary mechanics, reduce exposure to mechanical 
ventilation, and prevent PH. Although these improvements are not proven, improved 
pulmonary function and decreased risk of PH are potential benefits for participants 
enrolled in the study who receive sildenafil. Conclusions drawn from this study will 
benefit infants receiving sildenafil in the future through better understanding of dose 
response and characterization of the safety profile of sildenafil. 
3 OBJECTIVES AND OUTCOME MEASURES 
3.1 
Objectives 
3.1.1 Primary Objective 
Describe the safety of sildenafil in premature infants with severe BPD. 

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3.1.2 Secondary Objectives 
Analyze the pharmacokinetics (PK) and preliminary effectiveness of sildenafil in 
premature infants with severe BPD. 
3.1.3 Tertiary/Exploratory Objectives 
Explore other events of interest in premature infants with severe BPD.  
3.2 
Outcome Measures 
3.2.1 Primary Outcome Measures 
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. 
3.2.2 Secondary Outcome Measures 
3.2.2.1 
Pharmacokinetics 
A population PK analysis will be performed. Using the final population PK model, 
empirical Bayesian estimates of clearance, volume of distribution, and half-life will be 
generated for each participant and used to calculate exposure metrics (e.g. AUC, 
maximum concentration).  
3.2.2.2 
Preliminary Effectiveness 
The presence or absence of PH will be determined using central review by blinded 
pediatric cardiologists of echocardiograms performed at the end of the study period. 
The developed population PK model will be linked to the diagnosis of PH made by 
echocardiography at the end of the study period to develop a population PK/PD model. 
We will use the model to simulate the effect of variable sildenafil exposures on the 
probability of developing PH. 

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3.3 
Tertiary/Exploratory 
3.3.1 Other Safety and Efficacy Outcomes 
1. 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. 
2. Events of Special Interest: See Section 9.2.4 for a complete list of events of 
special interest (ESI). 
4 STUDY DESIGN 
Premature infants (inpatient in NICUs) 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. 
4.1 
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; including 
medications of special interest [Section 6.5.1]) 
7. Respiratory assessment (Section 8.2.2.3) 
8. Laboratory evaluations (Section 8.2) 
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  informed consent (Section 9.3) 
4.2 
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: 

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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 (including medications of special interest [Section 
6.5.1]) 
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: 
a. 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.  
b. For subsequent IV doses, the lowest valid MAP value should be 
recorded daily while on study drug.  
iii. If the administration route is enteral: 
a. 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. 
b. For subsequent enteral doses, the lowest valid MAP value should 
be recorded daily while on study drug. 
5. Respiratory assessment, daily (Section 8.2.2.3) 
6. Laboratory evaluations, at least once every 2 weeks (Section 8.2). 
7. Echocardiograms and cardiac catheterization reports, if performed per local 
standard of care 
8. PK sampling (after Day 7 [Section 8.2.2.1]) 
9. Adverse events (Section 9.3) 
4.3 
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, daily (Section 8.2.2.3) 

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4. Concomitant medications of special interest (Section 6.5.1) 
5. Echocardiogram and cardiac catheterization reports, if performed per local 
standard of care 
6. Adverse events (Section 9.3) 
4.4 
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, AEs, and 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, 7, 14, 21, and 28 should be 
recorded). 
3. Respiratory assessment, daily (Section 8.2.2.3) 
4. Laboratory evaluations obtained per local standard of care (Section 8.2) 
5. Concomitant medications of special interest (Section 6.5.1) 
6. 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. 
7. Echocardiograms and cardiac catheterization reports, if performed per local 
standard of care (during follow-up  Days 1-28) 
8. Adverse events and SAEs (during follow-up Days 1-28 [Sections 9.3]) 
4.5 
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 (Section 8.2.2.3)) 
3. Concomitant medications of special interest (Section 6.5.1) 
4. 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. 
5. Global rank (Section 8.2.2.4) 
6. Discharge information 
A. Discharge or transfer 
B. Death 
C. Duration of hospitalization 
7. Record if treatment for ROP was required 

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5 STUDY POPULATION 
5.1 
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.) 
5.2 
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 

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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. 
*Participant will be reassessed prior to dosing to reconfirm eligibility criteria. 
Note: Exclusion from participation due to enrollment in other clinical trials, including IND 
trials, will be left to the judgement of the site principal investigator (PI). Investigator 
judgement should consider the safety of the participant. 
5.3 
Strategies for Recruitment and Retention 
The study will include up to 120 premature infants (< 29 weeks gestation) with severe 
BPD (will screen approximately 600 infants). Potential subjects will be identified in the 
NICU at participating sites. Due to the nature of the condition, a minority population is 
intrinsically overrepresented (minority population represents 30-40% of infants with 
BPD; https://www.marchofdimes.org/peristats). Therefore, the study team does not 
anticipate difficulty with inclusion of individuals commonly underrepresented in research 
studies. 
Sites were selected based on prior participation in infant trials. Selected sites have 
research teams with extensive experience interacting with and enrolling the target 
population. Prior to and during the enrollment period for the study, sites will participate 
in conference calls to discuss recruitment and retention plans, including strategies for 
building rapport, increasing awareness, and enrolling the study population. 
Study staff will remain in frequent contact with patients/parents to ensure that the 
follow-up data are collected pre the protocol schedule. 
5.4 
Treatment Assignment Procedures 
5.4.1 Randomization Procedures 
 
Randomization will occur on Day -1 among participants who satisfy all eligibility criteria. 
Participants will be centrally randomized via the EDC to maintain a 3:1 ratio within each 
cohort of sildenafil (n=30) to placebo (n=10). Participants from a multiple gestation will 
be randomized independently as they become eligible. If more than one infant from a 
multiple gestation is randomized, the sibling relationship between participants will be 
collected in the eCRF.  
Reasons for premature discontinuation will be noted on the electronic case report form 
(eCRF). A randomized participant who prematurely discontinues from the study prior to 
receiving 7 days of study drug may be replaced with a new participant who will receive 
the same randomization assignment. Replacement will not be allowed if the reason for 
premature discontinuation is related to study drug (Safety Medical Monitor deems the 
event relationship as Possible, Probable, or Definite). The randomization process will 
not determine if an IV or enteral dose is used. Route of administration, IV or enteral, will 

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be left to investigator discretion. Participants should not have an IV placed specifically 
for study drug administration alone. However, if an investigator deems that a second IV 
would optimize the safe administration of other medications or fluids while the 
participant is receiving the study drug, then an additional IV is permissible. If the 
participant does not have an IV or if the clinical team elects to use enteral dosing, then 
the dose of study drug will be twice that of the IV dosing (from the product label). Infants 
may transition from enteral to IV sildenafil (and vice versa) throughout the duration of 
the study per the investigator’s determination. Placebo will be administered either 
enterally or IV in the same manner. 
Study randomization codes and replacement codes for all cohorts will be generated and 
uploaded prior to the enrollment of the first participant. One sequential dosing cohort will 
be available at a time for assignment. Subsequent cohort slots will only become 
available after completion of safety reviews. Unblinded results will only be shared with 
blinded members of the study team following database lock. Any unplanned unblinding 
of individual or treatment group-level data will be reported to the study PI. Unplanned 
unblinding will be reported to NHLBI Program Officer and the DSMB. 
5.4.2 Masking Procedures – Enteral Dosing 
Infants randomized to the placebo treatment group and receiving enteral study drug will 
receive the equivalent volume of dextrose 5% appropriate for enteral use. Staff 
accessing participant outcomes will be masked to treatment. Because prepared enteral 
sildenafil and placebo are visually slightly different, the pharmacy at each site will 
prepare and dispense the study drug into appropriate sized syringes in a masked 
manner (e.g., amber syringe, syringe overlay, etc.) in order to maintain masking of staff. 
Unmasking procedures are described in detail in the Manual of Procedures (MOP).  
5.5 
Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention 
5.5.1 Reasons for Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention 
The participant’s parent or guardian may withdraw an infant from participation in the 
study at any time. Parents or guardians can choose to have infant discontinue study 
drug and continue to be followed or they can withdraw consent for further participation 
at any time. 
The site investigator may choose to suspend study drug dosing once for up to 48 hours 
for any reason. If study drug is resumed by the site investigator, the dose and interval of 
the study drug will be the same as the prior dose. If applicable, subsequent doses will 
follow the dose escalation or weaning schedule as specified in section 6.1.  If study drug 
is suspended for > 48 hours, the study drug administration will be discontinued and the 
participant will proceed directly into the safety follow-up period, during which all 
remaining assessments will be collected. If study drug is suspended for > 48 hours for a 
documented safety concern, the suspension will not be considered a protocol deviation. 

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The site investigator will withdraw a participant from receiving further study 
interventions, including study drug administration, and the participant will enter the 28-
day safety-monitoring period if any of the following occur: 
o During the course of the study, the participant meets safety-related criteria that 
would have led to initial exclusion from study participation (i.e., ALT > 150 U/L, 
AST > 225 U/L, or infant started on vasopressor or inhaled nitric oxide 
[Section 5.2]). 
o Any clinically significant AE (e.g., hypotension) that is deemed by the site 
investigator to require discontinuation of study drug (see Section 9.5.3 for the 
definition of hypotension). 
o Unmasking of the participant treatment occurs. All unmasking events should be 
recorded on a protocol deviation form in the EDC system within 24 hours of the 
unmasking. The decision to unmask will be made in consultation with the medical 
monitor.  
Before discontinuing a participant from the study drug, the site investigator must contact 
the medical monitor or study PI, except in emergencies. All participants who have study 
drug suspended will continue to be in the study and complete all remaining study 
procedures in the safety follow-up period. 
5.5.2 Handling of Participant Withdrawals from Study or Participant 
Discontinuation of Study Intervention 
 
A randomized participant (Section 5.4.1) who prematurely discontinues from the study 
prior to receiving 7 days of study drug may be replaced with a new participant who will 
receive the same randomization assignment. Replacement will not be allowed if the 
reason for premature discontinuation is related to study drug (i.e., Safety Medical 
Monitor deems the event relationship as Possible, Probable, or Definite). 
Participants who are prematurely discontinued from receiving study drug for any reason 
will be followed for 28 days after last study drug dose for safety monitoring, and will 
have final study assessments collected. 
Reasons for participant withdrawal of consent or discontinuation from study drug will be 
appropriately documented by the site and captured in the appropriate eCRF, as 
instructed in the study eCRF Instructions provided to sites.  
The participant’s parent or guardian is not obligated to state the reason for withdrawal. 
The reasons for withdrawal, or decision not to provide a reason, must be documented 
by the investigator on the completion/withdrawal section of the corresponding eCRF. 
Participants/guardians who withdraw consent will not have any additional data entered 
in the EDC system. 

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5.6 
Premature Termination or Suspension of Study 
This study may be terminated at any time by the IND sponsor after consultation with 
FDA, NIH, and/or the Data Safety Monitoring Board DSMB. If the study is terminated, 
notification to FDA and US investigators will be made in accordance with 21 CFR 
312.56(d). 
If the study is discontinued, enrolled participants will continue to be followed for safety 
assessments through 28 days after last dose of study drug. All AEs must be followed 
through resolution. If the study is discontinued, regulatory authorities, IRBs and 
participant parents/guardians will be notified as required by regulation (e.g., U.S. 21 
CFR 312.56). 
6 STUDY INTERVENTION 
6.1 
Study Product Description 
In the US, sildenafil, in both IV and for oral suspension, has been approved for use in 
other populations and for other indications by the FDA1. 
Study dosing and escalation are described in Table 3. Refer to Section 6.1.3 for study 
drug packaging and labeling. 
Table 3 Number of Participants (N) and Dosing Scheme 
Cohort1 
Treatment Group 
Sildenafil Dosing2 
(mg/kg q 8 hours) 
Total (N) 
Placebo (N) 
Sildenafil (N) 
IV 
Enteral 
1 
10 
30 
0.5 
1 
40 
2 
10 
30 
1 
2 
40 
3 
10 
30 
2 
4 
40 
Abbreviations: IV, intravenous; N, number of participants; q, every 
1 Participants will be enrolled into cohorts sequentially (i.e., Cohort 1 then Cohort 2 then Cohort 3) 
based on safety. 
2 Route of administration, IV or enteral, is left to investigator discretion. 
 
Dose escalations for each sequential cohort will proceed as summarized in Table 4. 
DSMB safety review (Section 10) will be required prior to enrolling the next cohort. 

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Table 4 Dose Escalations for Each Sequential Cohort 
 
Study Days (Dose Numbers) 
1-2 
(1-6) 
3-4 
(7-12) 
5-6 
(13-18) 
7-8 
(19-24) 
9-10 
(25-30) 
11-12 
(31-36) 
13-14 
(37-42) 
15 + 
(43 +) 
Sildenafil Dose (mg/kg) 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
IV 
0.25 
0.5 
0.5 
0.5 
0.5 
0.5 
0.5 
0.5 
Enteral 
0.5 
1 
1 
1 
1 
1 
1 
1 
Cohort 2 
 
 
 
 
 
 
 
 
IV 
0.25 
0.5 
0.75 
1 
1 
1 
1 
1 
Enteral 
0.5 
1 
1.5 
2 
2 
2 
2 
2 
Cohort 3 
 
 
 
 
 
 
 
 
IV 
0.25 
0.5 
0.75 
1 
1.5 
1.75 
2 
2 
Enteral 
0.5 
1 
1.5 
2 
3 
3.5 
4 
4 
Abbreviation: IV, intravenous 
 
Dose escalation will occur if the infant is:  
1. Receiving exogenous oxygen or respiratory support (nasal cannula or positive 
pressure from any device); and 
2. AST < 225 U/L and ALT < 150 U/L at last check (within 14 days) prior and 
closest to dose increase. 
An infant will meet respiratory criteria for dose escalation only if the infant is receiving 
exogenous oxygen or respiratory support (nasal cannula or positive pressure from any 
device) for at least 12 hours before the dose escalation. Infants who do not initially 
qualify for escalation should be reevaluated daily to ascertain whether they meet these 
criteria, and escalation must occur within 24 hours of an infant meeting all dose 
escalation criteria (respiratory and laboratory). If escalation does not occur within this 
timeframe, then a protocol deviation must be recorded. 
Adjusting dose for weight 
The actual weight should be reviewed weekly (plus or minus one day, Section 4.2) and 
the dose of the study drug may be adjusted. 
Weaning Period Schedule 
Sildenafil is commonly used at higher doses to treat PH in infants. In clinical practice, it 
is recommended to wean from these higher doses to prevent rebound effects that may 
be seen with abrupt discontinuation of sildenafil. Although sildenafil used in this study is 
for prevention of PH, the target doses in Cohorts 2 and 3 are similar to those used for 
the treatment of PH.  
For Cohorts 2 and 3, weaning of study sildenafil or placebo will begin following the last 
study dose on Day 28 or if the dose escalates to a dose of ≥ 0.5 mg/kg IV or ≥1 mg/kg 
enteral and the participant is withdrawn from the study. Wean by 25% of last study dose 
every 2 days until off. Participants should complete weaning after 6 days (Table 5). 

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Table 5 Weaning Schedule for Study Sildenafil or Placebo in Cohorts 2 and 3 
Weaning Days 
IV 
Enteral 
1-2 
75% of last study dose 
75% of last study dose 
3-4 
50% of last study dose 
50% of last study dose 
5-6 
25% of last study dose 
25% of last study dose 
7 
Discontinue 
Discontinue 
Abbreviation: IV, intravenous 
 
If a participant in Cohort 2 or 3, escalates to a dose of ≥ 0.5 mg/kg IV (or ≥ 1 mg/kg 
enteral) and then is withdrawn from study drug, they will be withdrawn using the 
weaning schedule outlined above. Deviation from the weaning schedule for documented 
safety concerns will not result in a protocol deviation. 
Weaning is not required for participants in Cohort 1 as the risk of rebound effects is 
likely minimal for infants receiving low-dose sildenafil. 
6.1.1 Study Placebos 
Intravenous placebo is sterile saline or dextrose 5% and enteral placebo is dextrose 
5%. 
6.1.2 Acquisition 
Study drug and placebo will be acquired from the hospital pharmacy. Enteral sildenafil 
will be supplied to the site pharmacy by Pfizer, Inc. and will be labelled for 
investigational use. IV sildenafil will be supplied by the site using commercially available 
products (“off the shelf”). 
6.1.3 Formulation, Packaging, and Labeling 
Intravenous formulation: Only marketed IV formulation for IV administration will be used. 
This protocol will not specify the brand of product. Each product will be “off the shelf” as 
provided by the site’s pharmacy. Placebo will be an equal volume of sterile saline or 
dextrose 5%. 
Enteral formulation: The enteral formulation of sildenafil (Revatio®) will be provided for 
the study by Pfizer, Inc. Study drug will be shipped to each site pharmacy by the drug 
distribution vendor, Almac. Placebo will be an equal volume of dextrose 5%. 
Any requisite clinical trial materials will be provided with labeling in accordance with 
applicable regulatory requirements. Information regarding dosage, preparation and 
administration of study drug is detailed in Section 6.2 below. 

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6.1.4 Product Storage and Stability 
All study drugs must be stored in a secure area with access limited to the investigator 
and authorized site staff and under physical conditions that are consistent with product-
specific requirements provided in the product labeling.  
Detailed information on handling storing and reconstitution is found in the package 
insert. 
6.2 
Dosage, Preparation and Administration of Study Product 
The investigational pharmacist will be unmasked, and will prepare masked study drug. 
Detailed information will be included in the MOP. The pharmacy at each site will prepare 
and distribute the study drug in a masked manner and drug will be administered by the 
bedside nurse. 
Intravenous doses of study drug will be administered as infusion over 60 minutes 
followed by 30 minutes of flush. 
Enteral doses will be administered with feedings. The enteral formulation, if used, will be 
administered enterally either by mouth, orogastric, nasogastric, gastrostomy tube, or 
other enteral tubes. For enteral administration in infants receiving bolus feedings, mixing 
and timing of administration may follow the institutional policy. If there is no specific 
institutional policy, it is recommended that the study drug be mixed in 10 mL of feedings 
to be given at the end of the feed. If feeds are administered on pump, timing of 
administration may follow the institutional policy. If there is no specific institutional 
policy, it is recommended that study drug be mixed in the last 30 minutes of feeding 
volume. 
If the participant experiences signs or symptoms deemed by the investigator to be 
clinically significant hypotension or study drug-related SAE, the infusion or feeding will 
be stopped. Continued study drug administration will be decided by the clinical team. 
Refer to the MOP for specific details and recommendations for the use of IV and enteral 
dilutions for small drug volumes. 
6.3 
Modification of Study Product Administration for a Participant 
As noted in Section 6.1, dosing may be adjusted according to any weight changes 
determined at baseline, and study Days 7, 14 and 21. DSMB safety review is required 
prior to enrolling participants to the next cohort (Section 10). 
6.4 
Accountability Procedures for the Study Product 
Site pharmacies will have accountability for the study drug and placebo. Monitoring will 
be conducted to review compliance. 

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6.5 
Concomitant Medications/Treatments 
All drug and/or treatments are permitted while on study. Concomitant medications 
received within 24 hours prior to start of study drug and those given during the 28-day 
treatment period will be recorded. 
6.5.1 Concomitant Medications of Special Interest 
The following medications of special interest will be recorded for the entire study period:  
• Furosemide 
• Bumetanide 
• Chlorothiazide 
• Hydrochlorothiazide 
• Spironolactone 
• Inhaled nitric oxide 
• Bosentan 
• Epoprostenol sodium 
• Milrinone 
• Sildenafil 

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7 STUDY SCHEDULE  
7.1 
Table 6 
Schedule of Study Procedures 
 
Screen/ 
Baseline 
Treatment 
Weaning1 
Cohort 2 and 3 
Follow-up 
Final study 
assessment 
Time (Day) 
Predose2 
1-283 
(± 1 Day) 
Weaning  
Day 1-6 
Day 1-28 post 
last study drug 
dose 
Discharge or 
Transfer 
Informed consent 
X 
 
 
 
 
Randomization4 
X 
 
 
 
 
Demographics5 
X 
 
 
 
 
Physical examination 
X 
 
 
X (weekly) 
X 
Medical history 
X 
 
 
 
 
Actual Weight 
X 
X (weekly) 
 
X (weekly) 
X 
Mean arterial pressure  
X 
X 
Last day of wean X (weekly) 
 
Respiratory assessment 
X 
X6 (daily) 
X6 (daily) 
X6 (daily)   
X 
Laboratory evaluations7 
X 
X   (every 2 
weeks) 
X 
X 
 
Study drug administration 
 
X8 
X 
 
 
Concomitant medications 
X 
X 
X 
 
 
Concomitant medications 
of special interest9 
X 
X 
X 
X 
X 
Adverse events (including 
SAEs and ESIs)10 
X 
X 
X 
X 
 
Global Rank 
 
 
 
 
X 
Echocardiogram  
X 
X11 
X11 
X 
X11 
Cardiac catheterization 
reports11 
X 
X 
X 
X 
X 
PK sampling 
 
X (after 
Day 7) 
 
 
 
Discharge information, 
including ROP12 
 
 
 
 
X 
Abbreviations: AE, adverse event; PK, pharmacokinetics; PMA, postmenstrual age; ROP, retinopathy of prematurity; 
SAE, serious adverse event 
1 Weaning for Cohort 2 and 3 will begin following Day 28 or following the last day of study drug if participant was 
withdrawn from study drug prior to Day 28 and the dose was escalated to ≥ 0.5 mg/kg IV or ≥ 1 mg/kg enteral.  
2 Refers to < 24 hours (except laboratory evaluations) and < 14 days (for echocardiogram) prior to start of study drug 
that these procedures may be conducted and may be the same calendar date as Day 1; informed consent may be 
obtained any time prior to the initiation of any study procedures. 
3 Collect all safety follow-up and remaining assessments if early withdrawal of study drug occurs during the 28-day 
treatment period. AE and SAE follow-up is through 28 days post last dose of study drug.  
4Randomization will occur on Day -1 (1 day prior to first day of treatment).  
5 Participant demographics (including birthweight, gestational age at birth) and maternal race/ethnicity will be collected.  
6 Recorded daily during the treatment, weaning, and follow-up periods. 
7 If not performed per standard of care, AST and ALT must be performed within 72 hours prior to randomization and at 
least every 2 weeks  during the treatment period. When available, the following labs obtained during the treatment, 
weaning, and follow up periods will be recorded in the EDC if obtained per standard of care: ALT, AST, platelets, 
phosphorus, chloride, alkaline phosphatase, and caffeine levels.  
8 Dosing may be adjusted according to any weight changes determined at baseline, study Days 7, 14, and 21.  
9 Concomitant medications of special interest will be recorded during the entire study period.  
10 AEs will be collected following  informed consent through 28 days post last dose of study drug. 
11 If performed per local standard of care 
12 Transfer, discharge, duration of hospitalization or death; record if treatment for ROP was required. 

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8 STUDY PROCEDURES/EVALUATIONS 
8.1 
Study Procedures/Evaluations 
• A focused medical history of the participant will be extracted from the medical 
record. 
• Concomitant medication information including name, route of administration, and 
dose will be extracted from the medical record. 
• Physical examination including the vital signs (MAP) listed under the study 
schedule will be extracted from the medical record. 
• Echocardiogram images will be uploaded for central review and interpretation at 
the coordinating center. 
• Echocardiogram dates and reports will be collected in the EDC. 
• Cardiac catheterization dates and reports will be collected in the EDC. 
• Biological specimen collection will be performed per local procedures. See the 
MOP for further detail about biological specimen handling, storage, and shipping.  
• Respiratory assessments will be extracted from the medical record (see 
Section 8.2.2.3 for more details). 
• Discharge information will be extracted from the medical record. 
• Protocol-specified MAP values will be obtained per local procedures. 
• Blood pressure will be determined using MAP. For each participant, MAPs will be 
taken as noted in Section 4.2. Mean arterial pressure will be measured using an 
appropriate size cuff or with an intra-arterial placed catheter that measures 
continuous blood pressure. 
8.2 
Laboratory Procedures/Evaluations 
8.2.1 Clinical Laboratory Evaluations 
Laboratory evaluations for ALT and AST, if not already obtained per standard of care 
during the times indicated, must be conducted within 72 hours prior to randomization, 
and at least once every 2 weeks during the treatment period (at any time during the 2 
week period).  
If laboratory evaluations for ALT and AST are obtained more frequently than required by 
protocol, all results must be entered into the EDC system. 
Standard of Care laboratory evaluations:  When available, all values for ALT, AST, 
platelets, phosphorus, chloride, alkaline phosphatase, and caffeine levels within 
72 hours prior to randomization through 28 days following the last dose of study drug 
(include weaning doses) will be recorded. 

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8.2.2 Special Assays or Procedures 
8.2.2.1 PK Sampling 
Table 7 below provides the optimal PK sampling collection windows. Blood samples will 
be collected after any dose following the completion of 7 days (168 hours) of study drug 
administration at the target dose for that cohort. Every effort should be made to collect 
plasma samples within the windows; however, samples obtained outside of the 
sampling windows will not be considered protocol deviations. Sample collection 
windows are relative to the end of the infusion and flush (for IV administration); all 
samples should be collected after the flush. Blood samples should not be drawn during 
infusions or during the flush. Elimination samples will only be obtained around the last 
dose of study drug. 
Table 7 Target PK Sampling Times 
 
Intravenous or enteral per clinical care 
 
Time* 
PK # 
Enteral** 
Intravenous** 
1 
0–15 minutes 
0–15 minutes 
2 
30–60 minutes 
30–60 minutes 
3 
1-2 hours 
1-2 hours 
4 
2–3 hours 
2–3 hours 
5 
3–4 hours 
3–4 hours 
6 
4-5 hours 
4-5 hours 
7 
15 minutes prior to next dose 
15 minutes prior to next dose 
8^ (elimination) 
16–24 hours 
16–24 hours 
* Time is relative to the end of flush, which must be less than or equal to 30 minutes 
** May be drawn around more than 1 dose. 
**Sample is taken after dose of study drug (and flush if given by IV).  
^ Sample taken 16-24 hours after last dose. 
8.2.2.2 
Pharmacogenomics 
Because the major sildenafil metabolizing enzyme, CYP3A4/CYP3A5, is known to 
exhibit significant genetic polymorphisms altering its activity, we will evaluate 
polymorphisms as covariates in our PK model. Samples will be obtained from leftover 
cellular components of plasma samples. DNA samples will be identified by a code 
number, and other identifying information will be removed. Targeted genetic testing for 
CYP3A gene locus single nucleotide polymorphisms will be employed.  
8.2.2.3 Minimizing Blood Loss 
Blood samples will be collected in approximately 500 μL blood aliquots. To minimize the 
amount of blood sampling, a limited sampling scheme will be employed such that no 
more than 8 timed PK samples (4.0 mL of blood) are obtained from each participant for 
analysis. This amount of blood loss is safely within accepted 24-hour volumes for 
infants. Participants in all treatment groups (including placebo) will have samples 

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collected. Infants assigned to the placebo treatment group will have biomarkers of 
bronchopulmonary dysplasia measured instead of PK levels at a central laboratory 
(details in MOP; biomarkers may include NT-proBNP, IL-1, IL-6, IL-8, TNF-α). 
8.2.2.4 Respiratory Assessment 
The following information will be recorded daily during the treatment, weaning, and 
follow-up periods per the schedule of procedures tables:  
1) Fraction of inspired oxygen (FiO2): Blended O2 is defined as the maximum 
blended O2 on day of assessment, unless it is known to be a temporary (< 2 
hour) increase in blended O2. 
2) Highest level of ventilation type on day of assessment: 
a. High-frequency ventilator 
b. Conventional mechanical ventilator 
c. NCPAP (or equivalent, see Section 5.1) 
d. NIPPV  
e. Noninvasive NAVA 
f. Nasal cannula LPM 
g. None (room air with no support) 
3) Highest Mean Airway Pressure on day of assessment (if receiving invasive 
mechanical ventilation) 
8.2.2.5 Global Rank 
Each participant will receive a rank based upon the lowest ranking endpoint (1 = worst) 
that they experienced during their participation in the study. 
Details on clinical events and rank included in the global rank endpoint will be provided 
in the Statistical Analysis Plan.  
8.2.3 Specimen Preparation, Handling, and Storage 
See the MOP for further detail about biological specimen handling, storage, and 
shipping. 
8.2.4 Specimen Shipment 
See the MOP for further detail about specimen shipment. 
9 ASSESSMENT OF SAFETY 
9.1 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
The sponsor has engaged Duke Clinical Research Institute (DCRI) Safety Surveillance 
to oversee real-time SAE collection, evaluation, and expedited regulatory reporting for 
this study. A DCRI Safety Medical Monitor will be responsible for evaluating site 
reported SAEs to confirm protocol-specific serious reporting criteria, causality 

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assessment, and expectedness compared to the product label. Details of this process 
can be found in the study-specific Safety Management Plan. 
Safety will be assessed following informed consent through 28 days post last study drug 
dose (last study drug dose includes weaning doses). Safety will be assessed by 
frequency and incidence of the primary safety outcome (hypotension), events of special 
interest (ESI), and SAEs. A DSMB will be convened to review data and safety 
information from study participants throughout the study and prior to opening of 
Cohorts 2 and 3. 
Monitoring for hypotension, ESIs, and SAEs will occur from informed consent through 
28 days post last study drug dose (including the weaning doses). 
9.2 
Specification of Safety Parameters 
Safety parameters to be assessed include physical examination, weight, MAP, 
respiratory assessment, laboratory evaluations, echocardiograms, and cardiac 
catheterization reports. 
Safety events will be assessed and reported as described in the following sections. 
9.2.1 Unanticipated Problems 
The Office for Human Research Protections considers unanticipated problems involving 
risks to subjects or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
9.2.2 Serious Adverse Events 
An AE or Suspected Adverse Reaction (SAR) or Adverse Reaction is considered 
“Serious” if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event 
as it occurred) 

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• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
9.2.3 Serious Adverse Event Reporting Timelines 
Hypotension and SAEs will be entered into the EDC system within 24 hours of a site’s 
knowledge of the event. 
If the EDC system is temporarily unavailable, the SAE, including site 
investigator-determined relationship assessment (Section 9.4.1), should be reported to 
the sponsor’s Safety Surveillance via a paper back-up SAE form. Upon return of the 
availability of the EDC system, the most current SAE information must be entered on 
the AE/SAE eCRF. 
Events of special interest are to be entered into the EDC system within 7 days of a site’s 
knowledge of the event.  
Investigators must also submit safety reports locally as required by their IRB. 

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9.2.4 Events of Special Interest 
The patients enrolled in this trial are initially critically ill and are deemed to require 
prolonged NICU care. Such individuals are known to have a high morbidity and mortality 
rate. The following events will not be included in the primary safety outcome, but they 
are clinical ESI that may relate to safety and that will be tracked and reported in the trial 
results. These AEs are to be reported to study EDC, regardless of whether these events 
meet serious criteria or unexpectedness: 
• Sepsis, defined as positive blood culture with an organism not typically 
considered a contaminant.  
• Urinary tract infections, defined as a positive urine culture with an organism not 
typically considered a contaminant 
• Bacterial meningitis, defined as positive cerebrospinal fluid culture with an 
organism not typically considered a contaminant  
• Retinopathy of prematurity (ROP), defined as treatment with laser 
photocoagulation or an anti-VEGF drug 
• Seizures, determined by the treating provider 
• Abnormal hearing test results 
• Systemic arterial or deep venous thrombosis requiring treatment with 
anticoagulation (e.g., heparin or LMW heparin),  
• Direct hyperbilirubinemia, defined as conjugated serum bilirubin > 2.0 mg/dL 
• ALT > 150 U/L or AST > 225 U/L 
• Endotracheal intubation and transition from non-invasive to invasive ventilation, 
not due to planned surgical procedure (e.g., inguinal hernia repair or ROP 
treatment) 
9.2.5 Respiratory Support Escalation 
 
Sites will record the escalation from non-invasive ventilation to invasive ventilation in the 
EDC within 24 hours of knowledge of the escalation to invasive ventilation including the 
event, unless the escalation is due to a planned surgical procedure. If the reason for 
escalation to invasive ventilation met serious adverse event criteria, the site will record 
the final diagnosis as an SAE on the SAE eCRF. The DSMB will be notified of the 
escalation within 1-2 business days by the sponsor or designee.  
 
9.2.6 Time Period and Frequency for Event Assessment and Follow-Up 
The site investigator will record all SAEs and ESIs with a start date occurring from 
informed consent through 28 days after the last dose of study drug (last study drug dose 
includes weaning doses). 

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All hypotension and SAEs (study-drug related or not) must be followed until resolution. 
Events that cannot be resolved by 30 days after the safety-monitoring period will have 
the status of the ongoing event entered in the EDC system at that time. 
In cases when the participant has been transferred to another facility or discharged 
home, researchers may access test, treatment, and outcome information related to the 
event from the new treating facility and/or contact the participant/guardian. 
9.3 
Characteristics of an Adverse Event 
Each hypotension event, SAE and other clinical ESI will be assessed by the site 
investigator for the characteristics in the following sections. 
9.3.1 Relationship to Study Intervention 
The investigator will use the following question when assessing relatedness of an event 
of hypotension, ESI, or an SAE to study drug and study procedures, where an 
affirmative answer designates the event is a SAR:  
• Is there a reasonable possibility that the drug caused the event?  
‘‘Reasonable possibility’’ means that there is evidence to suggest a causal relationship 
between the drug and the adverse event. 
To assess relationship of an event to study intervention the following guidelines are 
used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention, and/or 
b. There is a temporal relationship between the intervention and event onset 
and/or 
c. The event abates when the intervention is discontinued, and/or 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event 
onset, and/or 
b. An alternate etiology has been established. 
9.3.2 Severity of Event 
The investigator should use the following definitions when assessing intensity of an 
event: 
1. Mild: Participant is aware of symptoms or has minor findings but tolerates them 
well, and no or minimal intervention required 
2. Moderate: Participant experiences enough symptoms or findings that may 
warrant intervention  
3. Severe: Participant experiences symptoms or findings that significantly affect 
clinical status and warrant intervention 

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9.4 
Adverse Event Reporting Procedures 
All hypotensive events and SAEs, as defined above, based on physical examination, 
laboratory findings, MAP measurements, or other means, will be reported in the EDC 
system within 24 hours of first knowledge of the event. The investigator or designated 
site personnel will record the required information regarding the hypotension, ESI, or 
SAE on the appropriate eCRF data fields including, relationship assessment to study 
drug, outcome, and whether the event met serious criteria. 
The DSMB will review hypotension and SAEs on a regular basis. In addition, a qualified 
and experienced clinician not otherwise associated with this protocol will serve as the 
Safety Medical Monitor. The Safety Medical Monitor will review valid SAEs at the time 
they are reported. If safety concerns are identified, the medical monitor may request a 
meeting of the DSMB to review safety data. At a minimum, the medical monitor will 
comment on the outcomes of the SAE and causal relationship of the SAE to the study 
drug. If no SAEs prompt review at an earlier time point, the DSMB will review safety 
events at the regularly scheduled meeting. Additionally, the DSMB will periodically 
review interim safety analyses (Section 10). The DSMB will convene and make 
recommendations on continuation of the study based on review of safety reports and 
halting rules.  
9.4.1 Expectedness  
The expectedness of a drug-related event (hypotension or SAE) will be determined 
according to the reference documents containing safety information (the package insert 
and the protocol). Any SAE that is not identified in nature, severity, or specificity in the 
current study package insert or protocol is considered unexpected. Events that are 
mentioned in the package insert or investigational plan as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but not 
specifically mentioned as occurring with the particular drug under investigation are 
considered unexpected. The study PI and/or study-appointed, clinically/medically 
-responsible individual will determine whether an AE is expected or unexpected. 
9.4.2 Reporting of Safety Events to FDA 
The Sponsor or designee will notify the FDA and all participating investigators in a 
written IND safety report of an SAR that, based on the opinion of the investigator or 
sponsor, is serious, is related to study drug, and is unexpected (per the sponsor) as 
soon as possible, but not later than 15 calendar days after the sponsor has determined 
the serious, unexpected SAR (SUSAR) qualifies for expedited reporting. ESI will not be 
reported as SUSARs. The sponsor will identify all safety reports previously filed with the 
IND concerning a similar SAR, and will analyze the significance of the SAR in light of 
the previous, similar reports. Follow-up reports will be sent to investigators to inform and 
update them about an important SAR if it significantly affects the care of the patients or 
conduct of the study. 
The site investigator will be responsible for reporting adverse events and unanticipated 
problems involving risks to patients to their local IRBs/IECs in accordance with local 
regulations.  

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9.4.3 Reporting of Hypotension 
If a hypotension event meets serious criteria, it will be reported as an SAE. 
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.  
9.4.4 Reporting of Pregnancy 
As the participants of this clinical trial are neonates, this section is not applicable. 
9.5 
Halting Rules 
9.5.1 Discontinuation of a Participant Due to Adverse Events 
Participants may be withdrawn from the study at any time. Participants withdrawn from 
the study due to a hypotensive event, ESI, or SAE must be followed by the investigator 
until the clinical outcome from the event is determined, or 28 days after the safety-
monitoring period, whichever comes first. Any participant who experiences an event 
may be withdrawn at any time from the study at the discretion of the investigator. The 
AE(s) resulting in discontinuation should be noted on the appropriate eCRFs, and the 
participant’s progress should be followed until the AE is resolved or considered stable. 
The medical monitor or project manager must be notified. If the AE may relate to 
overdose of study treatment, the package insert should be consulted for details of any 
specific actions to be taken. 
9.5.2 Unscheduled DSMB Review and Study Discontinuation 
An unscheduled DSMB review of safety data will be triggered if:  
• ≥ 3 patients in a cohort have treatment discontinued or an infusion stopped due 
to the same type of event; or  
• ≥ 3 patients in a cohort have a SAR. 
Enrollment will be suspended during DSMB review, although study activities will 
proceed on previously enrolled subjects as applicable.  
If the study is discontinued, enrolled participants will continue to be followed for safety 
assessments for 28 days. 
10 STUDY OVERSIGHT 
An independent DSMB will monitor the progress of the study to ensure study participant 
safety. Responsibilities of the DSMB will include review of accumulated safety data and 
assessments to ensure the safety of participating study participants and overall integrity 
of the study, provide recommendations regarding the further conduct of the study and 
identify any safety issues that may suggest risk to the participants enrolled in the study 

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or prospective participants. The DSMB will complete an unblinded review of the safety 
data after 80% of infants within the cohort complete 14 days of treatment. Enrollment to 
the next cohort will not begin until after the DSMB has completed their review and 
provided a recommendation that the study proceed. 
A DSMB charter will outline the membership, responsibilities, scope of activities, 
meeting frequency and communication plan between committee, sponsor, DCRI, and 
study sites. 
11 CLINICAL SITE MONITORING 
Clinical site monitoring will be conducted to ensure that human participant protection, 
study procedures, laboratory procedures, study intervention administration, and data 
collection processes are of high quality and meet sponsor, GCP/ICH, and regulatory 
guidelines, and that the study is conducted in accordance with the protocol and sponsor 
standard operating procedures. The IND sponsor, or its designee will conduct site-
monitoring visits as detailed in the Clinical Monitoring Plan (CMP). 
Most monitoring activities will be performed remotely, while other monitoring will take 
place at the study sites. Study team staff from the DCRI will conduct monitoring 
activities and provide reports of the findings and associated action items in accordance 
with the details described in the CMP. Documentation of monitoring activities and 
findings will be provided to the site study team. 
12 STATISTICAL CONSIDERATIONS 
12.1 Study Endpoints 
Primary safety endpoints are the incidence of hypotension. Secondary endpoints 
include PK and preliminary effectiveness (PK/PD). 
12.2 Sample Size Considerations 
The sample size of 30 (sildenafil) in each dose group is sufficient to estimate 
hypotension incidence with sufficient precision. Table 8 provides widths for 95% Wilson 
confidence intervals in the dose groups of size 30 and the total sildenafil treatment 
cohort of 90 with different incidence rates. If hypotension occurs with an incidence rate 
of 0.05, it has a 78% chance of being observed at least once in a dose group and a 
99% chance of being observed at least once in the total sildenafil cohort. 
Table 8 Widths for 95% Wilson Confidence Intervals 
N = 30 
N = 90 
Rate 
Width 
95% CI 
Rate 
Width 
95% CI 
0.1 
0.22 
0.04-0.26 
0.1 
0.13 
0.05-0.18 
0.2 
0.28 
0.10-0.37 
0.2 
0.16 
0.13-0.29 
0.3 
0.31 
0.17-0.48 
0.3 
0.19 
0.22-0.40 
Abbreviations: CI, confidence interval; N, number of participants 

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Populations for Analysis 
Intention to Treat (ITT) Population: Participants whose parent or guardian signs 
informed consent and are randomized.  
Per Protocol (PP) Population: Participants who receive at least 7 days of study 
medication within 9 days (to allow for one pause in medication administration for up to 
48 hours). 
Safety Population: Participants who receive at least 1 dose of study medication. 
PK Population: All participants who have at least one interpretable PK sample.  
12.3 Planned Interim Analyses 
12.3.1 Safety Review 
The DSMB will complete an unblinded review of the safety data after 80% of infants 
within the cohort complete 14 days of treatment. Enrollment to the next cohort will not 
begin until after the DSMB has completed their review and provided a recommendation 
that the study proceed. 
See Section 9.6 for additional details for halting rules due to safety concerns. 
12.4 Final Analysis Plan 
General Analysis Conventions 
A comprehensive overview of planned statistical analyses will be provided in a 
separated statistical analysis plan.  
Analysis results will be presented by placebo versus sildenafil, overall and by dose 
cohort. Data from participants assigned to placebo across cohorts will be pooled in 
result presentations. 
Descriptive statistics such as number of observations, mean, median, standard 
deviation, minimum and maximum will be presented by treatment groups for continuous 
variables (such as age, weight, etc.). Other descriptive statistics such as counts, 
proportions, and/or percentages will be presented by group to summarize discrete 
variables (such as race, sex, etc.). 
Participant Disposition and Study Drug Exposure 
Study disposition, demographic and baseline characteristics, and study medication 
exposure will be summarized for the ITT Population. Study drug administration will be 
summarized by route (IV vs enteral), number of days of dosing, and reasons for final 
discontinuation of study drug.  
Demographic and baseline characteristics 
Demographic and baseline characteristics will include race, age, sex, and selected 
clinical variables recorded prior to initiation of study drug.  

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Safety 
The primary safety endpoint is number and percent of hypotension events and will be 
summarized for the PP and Safety Population.  
Serious adverse events will be presented overall and by each Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred term. Severity and 
relationship to sildenafil or placebo will be provided.  
Events of special interest will be presented overall and summarized by participant 
characteristics. 
Prior and concomitant medications will be summarized by World Health Organization 
(WHO) drug class.  
Laboratory data, including change from baseline, will be tabulated by treatment groups. 
PK Analysis Plan 
A comprehensive overview of planned PK analyses will be provided in a separated PK 
analysis plan.  
Pharmacokinetic parameters will be estimated by population PK approach using 
nonlinear mixed effects modeling in NONMEM. The influence of covariates on PK 
parameters will be explored. 
Biomarkers 
We will relate the concentration of biomarkers (Section 8.2) to the development of and 
severity of PH in participants exposed to placebo. 
Preliminary Effectiveness 
A multivariable mixed-effects model will be used to explore the relationship between the 
maximum and total dose of sildenafil and change in PH, death, and death or PH at 28 
days of study drug and at the end of hospitalization or 52 weeks PMA, whichever comes 
first. We will use 52 weeks PMA because we found that 95% of infants with severe BPD 
died or were discharged home by this time.7 
Planned sensitivity analyses of the primary endpoint 
To address the potential effect of multiples enrolled in the study on the primary 
endpoint, we will conduct the following 2 sensitivity analyses:  
• Sensitivity analysis #1 using only the first randomized sibling from any multiple 
gestations.  
• Sensitivity analysis #2 using generalized estimating equations (GEE) with log link 
random effect for siblings to compute ratios of hypotension between the sildenafil 
and placebo groups.  

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13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
An eCRF will be used to record participation data. The eCRF will be used for the 
recording of all historical participant information and study data as specified by this 
protocol. The eCRF must be completed by designated and trained study personnel. 
According to ICH E6 (R2), source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents (original records or certified copies). 
Source documents are defined as original documents, data, and records (e.g., hospital 
records, clinical and office charts, laboratory notes, memoranda, participants’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
participant files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial).  
It will be the responsibility of the investigators to ensure that the regulatory binder at the 
site is maintained. The study file will contain, but will not be limited to: 
• Current package inserts, and all previous versions 
• Current study protocol 
• Protocol amendments (if applicable) 
• Manual of Procedures  
• Informed permission form (blank) 
• IRB approved informed permission form 
• Revised informed permission forms and/or all addenda (blank) 
• IRB registration or other documentation of IRB compliance with applicable 
regulations 
• Documentation of IRB/REB approval of protocol, permission form, any protocol 
amendments, and any permission form revisions 
• Annual IRB/REB updates and approvals 
• All correspondence between the investigator and IRB/REB 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with Section 4.9 of ICH E6 (R2), and regulatory and institutional 
requirements for the protection of confidentiality of participants. Each site will permit 
authorized representatives of the sponsor, its designees, and appropriate regulatory 
agencies to examine (and, when required by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits, and evaluation of the study safety 
and progress. These representatives will be permitted access to all source data. 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
The site investigator will provide direct access to all trial-related locations, source 
data/documents, eCRFs, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. The site investigator will 

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ensure that all study personnel are appropriately trained and applicable documentations 
are maintained on site. 
Clinical monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements. Clinical monitoring reports will be submitted to the 
PI. 
The DCRI will implement quality control procedures beginning with the data entry 
system and generate data quality control checks that will be run on the database. Any 
missing data or data anomalies will be communicated to the site(s) for prompt 
clarification and resolution. 
15 ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 Institutional Review Board 
Prior to enrollment of participants into this trial, the protocol, the informed parental 
permission form, and any materials or advertisements presented to participants or 
potential participants, will be reviewed and approved by the appropriate IRB.  
A copy of the letter of approval will be provided by the site study team to the sponsor. 
The institution’s federal-wide assurance number will be provided to the sponsor. 
If amendments to the protocol are required, the amendments will be written by the 
sponsor and provided to the investigator for submission and approval to the IRB. 
15.2 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continuing throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of participation in this study will be 
provided to the parents/legal guardians/legally authorized representatives (LARS) of 
participants in this study. Permission forms describing in detail the study purpose, 
duration, nature of participation and responsibilities of participants, procedures and risks 
are given to participants’ parents/guardians/LARs, and written documentation of 
informed permission is required prior to enrolling in the study.  
The participants’ parents/legal guardians/LARs will be asked to read and review the 
document, and the investigator will explain the research study and answer any 
questions that may arise. The participants’ parents/legal guardians/LARs will provide 
informed permission prior to the conduct of any study procedures. The participant’s 
parents/legal guardians/LARs should have the opportunity to think about the study prior 
to providing permission for the child to participate. The participants’ parents/legal 
guardians/LARs may withdraw permission at any time throughout the course of the 
study. A copy of the informed permission document will be given to the parent/legal 
guardian/LAR for their records. The rights and welfare of the participants will be 
protected by emphasizing to parents/legal guardians/LARs that the quality of medical 
care will not be adversely affected if they decline permission for the child to participate 
or withdraw from participating in this study. 

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Permission forms will be IRB-approved, and the IRBs will determine whether one parent 
or both parents must provide permission. It is the sponsor’s opinion, that because 
sildenafil is not part of the usual care for the patients who are eligible for enrollment that 
only one parent’s permission is needed. This is based on the following risk assessment: 
• 
Participants randomized to the placebo arm: These participants are receiving 
usual/standard of care which is no more than minimal risk. Per §46.404 only one 
parent’s permission is needed; 
• 
Participants randomized to the sildenafil arm: These participants are at more 
than minimal risk but are presented with the prospect of direct benefit. Per §46.405 only 
one parent’s permission is needed. 
Site staff may employ IRB-approved recruitment efforts prior to parent/legal 
guardian/LAR permission; however, before any protocol-specific procedures are 
performed to determine protocol eligibility, informed permission must be obtained and 
properly executed. 
By signing the permission form, the participant’s parent/legal guardian/LAR agrees that 
the participant will complete all evaluations required by the trial, unless the participant’s 
parent/legal guardian/LAR withdraws the participant voluntarily or the participant is 
withdrawn from the trial for any reason. 
The consent process will be documented in the research record. 
15.3 Exclusion of Women, Minorities, and Children (Special Populations) 
This is a study of the safety of sildenafil in premature infants with severe BPD. 
Individuals of any gender or racial/ethnic group who meet the inclusion/exclusion criteria 
for the study may participate.  
15.4 Subject Confidentiality 
Participant confidentiality is held strictly in trust by the participating investigators, their 
staff, and the study sponsor and their agents. This confidentiality is extended to cover 
testing of biological samples and genetic tests, in addition to the clinical information 
relating to participating participants. Participants will be assigned unique code numbers 
and will not be identifiable. Birth dates and date of death or discharge are collected in 
this study. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the study 
sponsor. 
The clinical study site will permit access to all documents and records that may require 
inspection by the sponsor, Regulatory Authorities or its authorized representatives, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. 

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In the US, the Health Insurance and Portability and Accountability (HIPAA) Privacy Rule 
applies. The rule provides US federal protection for the privacy of protected health 
information sent to or collected in the US for the purposes of this research by 
implementing standards to protect and guard against the misuse of individually 
identifiable health information of participants participating in clinical trials. “Authorization” 
is required from each research participant (i.e., specific permission granted by an 
individual to a covered entity for the use or disclosure of an individual’s protected health 
information). A valid authorization must meet the implementation specifications under 
the HIPAA Privacy rule. 
Certificate of Confidentiality 
To protect further the privacy of study participants, the Secretary, Health and Human 
Services (HHS), has issued a Certificate of Confidentiality to all researchers engaged in 
biomedical, behavioral, clinical, or other human subjects research funded wholly or in 
part by the federal government. Recipients of NIH funding for human subjects research are 
required to protect identifiable research information from forced disclosure per the terms of the 
NIH Policy (https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 
75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered 
by this Policy are required to establish and maintain effective internal controls (e.g., policies and 
procedures) that provide reasonable assurance that the award is managed in compliance with 
Federal statutes, regulations, and the terms and conditions of award. It is the NIH policy that 
investigators and others who have access to research records will not disclose identifying 
information except when the participant consents or in certain instances when federal, state, or 
local law or regulation requires disclosure. NIH expects investigators to inform research 
participants of the protections and the limits to protections provided by a Certificate issued by 
this Policy. 
NIH Data Sharing Policies  
As described in Section 17, it is NIH policy that the results and accomplishments of the activities 
that it funds should be made available to the public (see 
https://grants.nih.gov/policy/sharing.htm). PIs and funding recipient institutions will ensure 
that all mechanisms used to share data include proper plans and safeguards to protect the 
rights and privacy of individuals who participate in NIH-sponsored research. 
15.5 Future Use of Stored Specimens and Other Identifiable Data 
Biological samples collected as part of this study may be shipped periodically to the 
central laboratory(s) for protocol defined testing (e.g., drug concentration measurements 
of PK samples). 
After the study is completed, residual biological samples (e.g., plasma) from this study 
will be submitted to an NIH storage facility in accordance with applicable privacy laws 
and/or IRB determinations. These samples will not include any personal identifiers. 
They will be labeled with a unique code. The NIH repository will not have access to any 
personally identifying participant information. With NIH approval, the de-identified study 
samples may be made available to other researchers. 

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Parents/legal guardians/LARs are asked to provide informed consent/permission for the 
biological sample collection process, specimen repository, and potential for future 
research prior to the child’s participation in the study. 
16 DATA HANDLING AND RECORD KEEPING 
US investigators are obligated to conduct this study in accordance with US Federal 
Regulation 21 CFR 312.60-69 as specified on the signed form FDA 1572, applicable 
local laws, and the ICH: GCP: Consolidated Guidance (ICH E6[R2]). 
The investigator is responsible for informing the IRB of any safety issues related to the 
study and the study drug, including reports of SAEs, if required, and all expedited safety 
reports. 
The investigator is responsible for ensuring that attributable, legible, contemporaneous, 
original, accurate, and complete data or records are recorded and reported. 
Data reported in the eCRF should be consistent with the source documents, or the 
discrepancies should be documented. The sponsor and/or its designee will provide 
guidance to investigators on making corrections to the eCRFs and eCRF. 
16.1 Data Management Responsibilities 
All eCRFs and laboratory reports must be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. Adverse events must be 
graded, assessed for severity and causality, and reviewed by the site PI or designee. 
Data collection is the responsibility of the study staff at the site under the supervision of 
the site PI. During the study, the investigator must maintain complete and accurate 
documentation for the study. 
The DCRI will be responsible for data management, quality review, analysis, and 
reporting of study data. 
16.2 Data Capture Methods 
Clinical data (including SAEs and concomitant medications) will be entered into a 21 
CFR Part 11-compliant internet data entry system provided by the DCC. The data 
system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from source documents. 
16.3 Types of Data 
We will collect clinical and pharmacokinetic laboratory data. Safety data will include 
blood pressure measures, hypotension events, events of special interest and SAEs. 
Outcome data includes clinical diagnoses, echocardiograms and their reports, and 
cardiac catheterization reports.  
16.4 Schedule and Content of Reports 
Not applicable  

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16.5 Study Records Retention 
The investigator must retain all study records and source documents for a minimum of 
2 years following the completion of the study, unless the sponsor requests longer 
retention, or local regulations and institutional policies require longer retention. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another investigator, 
IRB). Notice of such transfer will be given in writing to the sponsor. 
16.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol. The 
noncompliance may be on the part of the participant, the investigator, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
These practices are consistent with GCP: 
4.5. Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1. Quality Assurance and Quality Control, Section 5.1.1 
5.2. Noncompliance, Sections 5.20.1, and 5.20.2 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation or within 
5 working days of the scheduled protocol-required activity. All deviations must be 
promptly reported to the sponsor, via the DCC’s EDC. 
All deviations from the protocol must be addressed in study eCRFs. A completed copy 
of the protocol deviation form must be maintained in the regulatory file. Protocol 
deviations must be submitted to the local IRB per their guidelines. The site PI/study staff 
is responsible for knowing and adhering to their IRB requirements. 
17 PUBLICATION/DATA SHARING 
Following completion of the study, the investigator may publish the results of this 
research in a scientific journal. All public presentations (abstracts, manuscripts, slides 
and text of oral or other presentations, and text of any transmission through any 
electronic media) by participating investigators, participating institutions, and DCC, will 
be reviewed by the Publication Committee per the Publication Committee charter. 
The Publication Committee guarantees that the study results are presented by experts 
in the field that have working knowledge of the study design, implementation, data 
synthesis/analysis, and interpretation. The committee goals are to ensure that any 
confidential or proprietary information is protected, and that all appropriate statistical 
analyses have been included. 
The Publication Committee will adhere to the trials registration policy adopted by the 
International Committee of Medical Journal Editors (ICMJE) member journal. This policy 
requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other 

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biomedical journals are considering adopting similar policies. It is the responsibility of 
the IND holder to register this trial in an acceptable registry. 
All investigators funded by the NIH must submit or have submitted for them to the 
National Library of Medicine’s PubMed Central an electronic version of their final, peer 
-reviewed manuscripts upon acceptance for publication, to be made publicly available 
no later than 12 months after the official date of publication. Refer to 
http://publicaccess.nih.gov/ and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-
08-033.html. 
This study will comply with all applicable NIH Data Sharing Policies. See 
https://grants.nih.gov/policy/sharing.htm for policies and resources. 
NIH Public Access Policy 
The NIH Public Access Policy requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to PubMed Central immediately upon acceptance 
for publication. This ensures that the public has access to the published results of NIH 
funded research.  
 NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information 
The study is a clinical trial and will comply with the NIH policy that establishes the 
expectation that all investigators conducting clinical trials funded in whole or in part by 
the NIH will ensure that these trials are registered at ClinicalTrials.gov, and that results 
of these trials are submitted to ClinicalTrials.gov.   
Food and Drug Administration Amendments Act of 2007 (FDAAA) and the Final Rule for 
Clinical Trials Registration and Results Information Submission 
This study is an applicable clinical trial and will comply with U.S. Public Law 110-85 
(Food and Drug Administration Amendments Act of 2007 or FDAAA), Title VIII, Section 
801 and 42 CFR Part 11 (HHS Final Rule for Clinical Trials Registration and Results 
Information Submission), which mandate that a "responsible party" (i.e., the sponsor or 
designated principal investigator) register and report results of "applicable clinical trials."  

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