Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia
Phase: PHASE2
Conditions: Bronchopulmonary Dysplasia
Sponsor: University of North Carolina, Chapel Hill

 
Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary 
Dysplasia 
NCT number NCT03142568 
Document Date 04/03/2023 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
i 
CONFIDENTIAL 
 
 
 
Pediatric Trials Network: Best Pharmaceuticals for Children Act  
 
Safety of Sildenafil in Premature Infants at Risk of 
Bronchopulmonary Dysplasia 
 
Protocol Number: NICHD-2015-SIL02 
 
Phase 2 Trial 
 
Funding Sponsor: 
 
The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) 
 
Funding Mechanism: Task Order 
 
Protocol Date: 
03APR2023 
Protocol Version: 
7.0 
IND Number: 
112374 
IND Sponsor and 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 
E-mail: matt_laughon@med.unc.edu 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
ii 
CONFIDENTIAL 
 
STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Council for Harmonisation 
(ICH) E6 (R2) Guideline for Good Clinical Practice, and the applicable regulatory requirements of the 
United States and Canada. The US regulations include but are not limited to 45 CFR 46 (Human 
Subjects Protection); 45 CFR 160 and 164 Subparts A and E (HIPAA Privacy Rule); 21 CFR 
312 (Investigational New Drug Application); 21 CFR 50 (Protection of Human Subjects, including 
Subpart D - Additional Safeguards for Children in Clinical Investigations); and 21 CFR 56 (Institutional 
Review Boards [IRB]). Applicable Canadian legislation includes: the Food and Drug Act, the Food and 
Drug Regulations Part C Division 5, and Federal and Provincial Acts and Regulations respecting 
privacy and/or protection of personal information including health and genetic information. 
All individuals responsible for the design and/or conduct of this study have completed Human Subjects 
Protection Training and are qualified to be conducting this research. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
iii 
CONFIDENTIAL 
 
SITE PRINCIPAL INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the investigator brochure or product label, and I 
agree that it contains all necessary details for my staff and me to conduct this study as described. I will 
personally oversee the conduct of this study as outlined herein and will make a reasonable effort to 
complete the study within the time designated. I agree to make all reasonable efforts to adhere to the 
attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to all 
information provided by the sponsor or the sponsor’s representative. I will discuss this material with 
study personnel to ensure that they are fully informed about the efficacy and safety parameters and the 
conduct of the study in general. I am aware that, before beginning this study, the Institutional Review 
Board (IRB) or Research Ethics Board (REB) responsible for such matters must approve this protocol 
in the clinical facility where it will be conducted. 
I agree to obtain informed consent forms from participants’ parent/legal guardian, as required by 
government regulations and International Conference on Harmonisation guidelines. I further agree to 
report to the sponsor or its representative any adverse events in accordance with the terms of this 
protocol; the U.S. Code of Federal Regulations, Title 21, part 312.64 (US sites); Part C Division 
05.014 and C.05.012 (3) (f)(i) of the Canadian Food and Drug Regulations; and ICH GCP 4.11. 
 
 
 
 
 
 
Principal Investigator Name (Print) 
Signature 
Date 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
iv 
CONFIDENTIAL 
 
STUDY PRINCIPAL INVESTIGATOR AND IND SPONSOR 
SIGNATURE 
The signature below documents the review and approval of this protocol and the attachments (e.g., 
package inserts), and provides the necessary assurances that this clinical 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 to the principles outlined in applicable U.S. 
federal regulations or Canadian federal and provincial laws and regulations (as applicable) and ICH 
guidelines. 
 
 
 
 
 
Matthew M. Laughon, MD, MPH 
Pediatric Trials Network Study Principal Investigator Name 
Signature 
Date 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
v 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ......................................................................................................... ii 
SITE PRINCIPAL INVESTIGATOR STATEMENT ............................................................................... iii 
STUDY PRINCIPAL INVESTIGATOR AND IND SPONSOR SIGNATURE .......................................... iv 
TABLE OF CONTENTS........................................................................................................................ v 
LIST OF ABBREVIATIONS ............................................................................................................... viii 
PROTOCOL SYNOPSIS ...................................................................................................................... x 
1. 
KEY ROLES ............................................................................................................................... 1 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................................... 2 
2.1 
Background Information ............................................................................................................. 2 
2.2 
Scientific Rationale ..................................................................................................................... 2 
2.3 
Potential Risks and Benefits ....................................................................................................... 9 
2.3.1 
Potential Risks ................................................................................................................ 9 
2.3.2 
Potential Benefits .......................................................................................................... 10 
3. 
OBJECTIVES AND OUTCOME MEASURES ............................................................................ 11 
3.1 
Objectives ................................................................................................................................ 11 
3.1.1 
Primary Objective .......................................................................................................... 11 
3.1.2 
Secondary Objective ..................................................................................................... 11 
3.2 
Outcome Measures .................................................................................................................. 11 
3.2.1 
Primary Outcome Measures .......................................................................................... 11 
3.2.2 
Secondary Outcome Measures ..................................................................................... 11 
3.2.3 
Other Safety and Efficacy Outcomes ............................................................................. 11 
4. 
STUDY DESIGN ....................................................................................................................... 13 
5. 
STUDY POPULATION ............................................................................................................. 14 
5.1 
Selection of the Study Population ............................................................................................. 14 
5.2 
Inclusion/Exclusion Criteria ....................................................................................................... 14 
5.2.1 
Inclusion Criteria ........................................................................................................... 14 
5.2.2 
Exclusion Criteria .......................................................................................................... 14 
5.3 
Treatment Assignment Procedures ........................................................................................... 14 
5.3.1 
Additional Participants .................................................................................................. 14 
5.3.2 
Randomization Procedures ........................................................................................... 14 
5.3.3 
Masking Procedures ..................................................................................................... 15 
5.3.4 
Reasons for Participant Withdrawal ............................................................................... 15 
5.3.5 
Termination of Study ..................................................................................................... 16 
6. 
STUDY PROCEDURES ........................................................................................................... 17 
6.1 
Summary of Procedures ........................................................................................................... 17 
6.2 
Screen/Baseline ....................................................................................................................... 18 
6.3 
Treatment Period ...................................................................................................................... 18 
6.4 
Weaning Period (Cohorts 2 and 3) ............................................................................................ 19 
6.5 
Follow-up Period ....................................................................................................................... 19 
6.6 
36-week PMA Assessment ....................................................................................................... 19 
6.7 
Final Study Assessment ........................................................................................................... 20 
6.8 
Respiratory Assessment ........................................................................................................... 20 
6.9 
Laboratory Evaluations ............................................................................................................. 20 
6.10 
PK Sampling ................................................................................................................. 21 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
vi 
CONFIDENTIAL 
 
6.10.1 Minimizing Blood Loss ................................................................................................... 21 
6.10.2 Specimen Preparation, Handling, and Shipping ............................................................ 22 
6.11 
Adverse Event .............................................................................................................. 22 
7. 
STUDY DRUG DESCRIPTION ................................................................................................ 23 
7.1 
Dosage and Study Drug Information......................................................................................... 23 
7.1.1 
Adjusting dose for weight: ............................................................................................. 24 
7.2 
Weaning Period Schedule: ....................................................................................................... 24 
7.3 
Formulation, Packaging, and Labeling ...................................................................................... 25 
7.4 
Preparation and Administration of Study Intervention/Study Drug ............................................ 25 
7.5 
Product Storage and Stability ................................................................................................... 25 
7.6 
Concomitant Medications/Treatments ...................................................................................... 25 
8. 
ASSESSMENT OF SAFETY .................................................................................................... 26 
8.1 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters ................... 26 
8.1.1 
Adverse Event .............................................................................................................. 26 
8.1.2 
Unexpected Adverse Event or Reaction ........................................................................ 26 
8.1.3 
Identification of Events and Timeframe for Reporting .................................................... 26 
8.1.4 
Low Blood Pressure and Hypotension .......................................................................... 27 
8.1.5 
Primary Definition of Hypotension ................................................................................. 27 
8.1.6 
Presumed low blood pressure and presumed hypotension ............................................ 27 
8.1.7 
Follow-up of Adverse Events ........................................................................................ 27 
8.1.8 
Guidelines for Assessing Intensity of an Adverse Event ................................................ 28 
8.1.9 
Guidelines for Determining Causality ............................................................................ 28 
8.1.10 Discontinuation of a Participant Due to Adverse Events ................................................ 28 
8.1.11 Investigator Reporting Procedures ................................................................................ 28 
8.2 
Serious Adverse Events ........................................................................................................... 28 
8.3 
Regulatory Reporting ............................................................................................................... 28 
8.4 
Safety Oversight ....................................................................................................................... 29 
8.5 
Halting Criteria: Safety Concerns ............................................................................................. 29 
9. 
CLINICAL MONITORING ......................................................................................................... 30 
10. 
STATISTICAL CONSIDERATIONS .......................................................................................... 31 
10.1 
Study Endpoints ............................................................................................................ 31 
10.2 
Sample Size Considerations ......................................................................................... 31 
10.3 
Interim Safety Analysis ................................................................................................. 31 
10.4 
Analysis Plan ................................................................................................................ 32 
10.4.1 Descriptive statistics ..................................................................................................... 32 
10.4.2 Demographic and baseline characteristics ..................................................................... 32 
10.4.3 Safety 32 
10.4.4 Effectiveness analysis ................................................................................................... 32 
10.4.5 PK analysis plan ........................................................................................................... 32 
10.4.6 Biomarkers ................................................................................................................... 32 
11. 
PARTICIPANT CONFIDENTIALITY ......................................................................................... 33 
12. 
INFORMED CONSENT PROCESS .......................................................................................... 34 
13. 
FUTURE USE OF SPECIMENS ............................................................................................... 35 
14. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .......................... 36 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 37 
16. 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................. 38 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
vii 
CONFIDENTIAL 
 
16.1 
Ethical Standard ........................................................................................................... 38 
16.2 
Institutional Review Board/Research Ethics Board ....................................................... 38 
16.3 
Informed Consent ......................................................................................................... 38 
16.4 
Study Discontinuation ................................................................................................... 38 
17. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 39 
17.1 
Data Management Responsibilities ............................................................................... 39 
17.2 
Data Capture Methods .................................................................................................. 39 
17.3 
Timing/Reports ............................................................................................................. 39 
17.4 
Study Records Retention .............................................................................................. 39 
17.5 
Protocol Deviations ....................................................................................................... 40 
17.6 
Participant Privacy/Authorization................................................................................... 40 
18. 
PUBLICATION POLICY ........................................................................................................... 41 
19. 
LITERATURE REFERENCES .................................................................................................. 42 
 

NI C H D -2 0 1 5 -SI L 0 2  – SI L D E N A FI L    
  
  
  
  
  
  
 
        V er si o n  7. 0  
I N D # 1 1 2 3 7 4  
  
  
  
  
  
   
 
                
 
       0 3 A P R 2 0 2 3 
 
viii  
C O N FI D E N TI A L  
 
LI S T  O F  A B B R E VI A TI O N S 
 
A b br e vi ati o n  
D efi niti o n  
A E  
A d v er s e  E v e nt  
A L T  
Al a ni n e  A mi n otr a n sf er e s e  
A S T  
A s p art at e  A mi n otr a n sf er e s e  
A U C 0 -2 4  
Ar e a  U n d er  t h e C o n c e ntr ati o n  Ti m e  C ur v e  0 -2 4  h o ur s  
A U C s s  
Ar e a  U n d er  t h e C o n c e ntr ati o n  Ti m e  C ur v e  at  St e a d y  St at e  
B P D  
Br o n c h o p ul m o n ar y  D y s pl a si a  
C F R  
C o d e  of  F e d er al  R e g ul ati o n s  
C L  
Cl e ar a n c e  
C m a x  
M a xi m u m  C o n c e ntr ati o n  
C R F  
C a s e  R e p ort  F or m  
D C C  
D at a  C o or di n ati n g  C e nt er  
D C RI  
D u k e  Cli ni c al  R e s e ar c h  I n stit ut e 
D S M B  
D at a S af et y M o nit ori n g B o ar d  
e C R F  
El e ctr o ni c  C a s e  R e p ort  F or m  
E D C  
El e ctr o ni c  D at a  C a pt ur e  s y st e m  
Fi O 2  
Fr a cti o n  of  I n s pir e d O x y g e n  
F D A  
F o o d  a n d Dr u g  A d mi ni str ati o n  
G A  
G e st ati o n al  A g e  
G C P  
G o o d  Cli ni c al  Pr a cti c e  
HI P A A  
H e alt h  I n s ur a n c e P ort a bilit y  a n d  A c c o u nt a bilit y  A ct  
H F N C  
Hi g h  Fl o w  N a s al  C a n n ul a  
I C F 
I nf or m e d C o n s e nt  F or m  
I C H 
I nt er n ati o n al C o nf er e n c e  o n  H ar m o ni s ati o n  
I C M J E 
I nt er n ati o n al C o m mitt e e  of  M e di c al  J o ur n al  E dit or s  
I D E S 
I nt er n et D at a  E ntr y  S y st e m  
I E C 
I n d e p e n d e nt or  I n stit uti o n al Et hi c s  C o m mitt e e  
I N D 
I n v e sti g ati o n al N e w  Dr u g  A p pli c ati o n  
I R B 
I n stit uti o n al R e vi e w  B o ar d  
I V 
I ntr a v e n o u s 
K g  
Kil o gr a m  
L  
Lit er  
L P M  
Lit er s  p er  Mi n ut e  
M e d D R A
 
M e di c al  Di cti o n ar y  f or R e g ul at or y  A cti viti e s  
m g  
Milli gr a m  
μ g  
Mi cr o gr a m  
M A P  
M e a n  Art eri al  Pr e s s ur e  
m m  H g  
Milli m et er  of  m er c ur y  
M O P  
M a n u al  of  Pr o c e d ur e s  
N  
N u m b er  (t y pi c all y r ef er s t o p arti ci p a nt s)  
N C P A P  
N a s al  C o nti n u o u s  P o siti v e  Air w a y  Pr e s s ur e  
N -D M S  
N -D e s -m et h yl  Sil d e n afil  
NI C U  
N e o n at al  I nt e n si v e C ar e  U nit  

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
ix 
CONFIDENTIAL 
 
Abbreviation 
Definition 
NIH 
National Institutes of Health 
NRN 
Neonatal Research Network 
PAH 
Pulmonary Arterial Hypertension 
PDA 
Patent Ductus Arteriosus 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PMA 
Postmenstrual age (gestational age plus postnatal age) 
PNA 
Postnatal age 
PO 
Per os (by mouth) 
PTN 
Pediatric Trials Network 
q 
Every 
ROP 
Retinopathy of Prematurity 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
SOC 
Standard of Care 
TORO 
Transfer of Regulatory Obligations 
t1/2 
Half-life 
U/L 
Units per liter 
WHO 
World Health Organization 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
x 
CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
 
Protocol Title: 
Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary 
Dysplasia (BPD) 
Phase: 
2 
Product: 
Sildenafil citrate injection and powder for suspension 
Objectives: 
Primary: Describe the safety of sildenafil in premature infants at risk of BPD 
Secondary: Preliminary effectiveness and pharmacokinetics (PK) of sildenafil 
Study Design: 
Multi-center, randomized, placebo-controlled, sequential dose escalating, double 
masked, safety study 
Study 
Population: 
Inclusion Criteria 
1. Documented informed consent from parent or guardian, prior to study 
procedures 
2. Receiving positive airway pressure (nasal continuous airway pressure, 
nasal intermittent positive pressure ventilation, or nasal cannula flow 
> 1LPM) or mechanical ventilation (high frequency or conventional) at the 
time of randomization* 
3. < 29 weeks gestational age at birth 
4. 7-28 (inclusive) days postnatal age at time of randomization* 
Exclusion Criteria 
1. Previous enrollment and dosing in NICHD-2015-SIL02 Safety of Sildenafil 
in Premature Infants at Risk of Bronchopulmonary Dysplasia” 
2. Previous exposure to sildenafil within 7 days prior to randomization* 
3. Currently receiving vasopressors* 
4. Currently receiving inhaled nitric oxide* 
5. Baseline mean arterial pressure (MAP) < gestational age (in weeks) plus 
postnatal age (in weeks) within 24 hours of randomization*; e.g. an infant at 
25 weeks gestational age and 3 weeks postnatal age with MAP < 28 mm 
Hg would be ineligible 
6. Known allergy to sildenafil 
7. Known sickle cell disease 
8. AST > 225 U/L < 72 hours prior to randomization* 
9. ALT > 150 U/L < 72 hours prior to randomization* 
10. Any condition which would make the participant, in the opinion of the 
investigator, unsuitable for the study* 
*Participant will be re-assessed prior to dosing to reconfirm eligibility criteria 
Number of 
Participants: 
Up to 120 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
        Version 7.0 
IND # 112374 
 
 
 
 
 
  
 
              
 
       03APR2023 
 
xi 
CONFIDENTIAL 
 
Number of 
Sites: 
Approximately 30 sites 
Duration of 
Participation: 
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 post menstrual age 
and/or at discharge. 
Dose 
Schedule: 
Note: Participants will be enrolled into cohorts sequentially (i.e. cohort 1 then cohort 2 then cohort 3) 
based on safety. Route of administration should be via IV route if patient has IV and is feasible, but 
choice is left to the discretion of investigator. 
 
 
Table. N and dosing scheme 
N 
Sildenafil 
(IV) 
Sildenafil 
(enteral) 
N 
Cohort 
Total N 
Cohort 1 
Placebo 
10 
0.125 mg/kg q 
8 hours 
0.25 mg/kg q 
8 hours 
30 
40 
Cohort 2 
Placebo 
10 
0.5 mg/kg q 8 
hours 
1 mg/kg q 8 
hours 
30 
40 
Cohort 3 
Placebo 
10 
1 mg/kg q 8 
hours 
2 mg/kg q 8 
hours 
30 
40 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
1 
CONFIDENTIAL 
 
1. KEY ROLES 
For questions regarding this protocol, contact: 
 
Study Principal Investigator 
IND Sponsor (US),  
and Senior Executive Officer (Canada): 
 
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 
Email: matt_laughon@med.unc.edu 
Senior Medical Officer (Canada) 
Thierry Lacaze, MD, PhD 
Professor and Section Head 
Neonatology, Department of Pediatrics 
University of Calgary 
Foothills Medical Centre 
780 – 1403 29th Street NW 
Calgary, Alberta, T2N 2T9 
Tel: 403-944-4638 
Email: 
Thierry.Lacaze-Masmonteil@albertahealtservices.ca 
Sub-Investigators: 
Sub-investigators are included in the signature log 
and consent form(s) at each clinical site. 
Medical Monitor: 
Jill Schwartz, MD, Medical Director 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Telephone: 301-251-1161 
Email: bpcasafety@emmes.com 
BPCA DCC Principal Investigator: 
 
Ravinder Anand, PhD, Vice President 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Telephone: 301-251-1161 / Fax: 1-800-784-9044  
Email: SIL02@emmes.com 
NICHD Contract Officer Representative: 
Perdita Taylor-Zapata, MD 
National Institutes of Health 
Eunice Kennedy Shriver National Institute for Child 
Health and Human Development 6710B 
Rockledge Drive 
Bethesda, MD 20892 
Telephone: 301-594-8670 
Fax: 301-480-7773 
Email: taylorpe@mail.nih.gov 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
2 
CONFIDENTIAL 
 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
Section 409I of the Public Health Service Act, also known as the Best Pharmaceuticals for Children 
Act (BPCA), mandates the National Institutes of Health (NIH) to prioritize therapeutic areas in critical 
need for pediatric labeling; to sponsor pediatric clinical trials; and to submit data to FDA for 
consideration for labeling changes. Under the BPCA, the National Institute for Child Health and Human 
Development (NICHD) awarded a contract to Duke University, which established the Pediatric Trials 
Network (PTN) through its Duke Clinical Research Institute (DCRI). The NICHD awarded a separate 
contract to The Emmes Company, LLC to serve as the BPCA Data Coordinating Center (DCC). 
2.2 
Scientific Rationale 
Bronchopulmonary dysplasia (BPD) is defined by the NIH as mild, moderate, or severe based on 
required respiratory support at 36 weeks postmenstrual age.1 An NIH workshop proposed a 
severity -based definition that classifies BPD into mild, moderate or severe based on either postnatal 
age (PNA) or postmenstrual age (PMA) (Table 2-1). Ehrenkranz et al2 validated the NICHD 
severity -based definition of BPD by comparing it to the more traditional definitions of BPD such as 
supplemental oxygen at 28 days and at 36 weeks PMA. The NICHD consensus severity based scale 
better identified infants who are at most risk for poor pulmonary outcomes as well as neurodevelopment 
impairment than the traditional definitions.2 
Table 2-1. NICHD severity-based definition of BPD for premature infants at 36 weeks post 
menstrual age (or discharge) 
No BPD 
Receiving > 21% supplemental oxygen (O2) for ≤28 days and not at 36 weeks PMA 
Mild BPD 
Receiving > 21% O2 for ≥28 days but not at 36 weeks PMA 
Moderate BPD Receiving > 21% O2 for ≥28 days plus treatment with <30% O2 at 36 weeks PMA 
Severe BPD 
Receiving > 21% O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36 weeks PMA 
 
BPD is characterized by clinical signs and symptoms as well as pathologic findings in the lung. 
The most common form of BPD is mild or moderate BPD. Animal studies suggest that the histology of 
infants with mild or moderate BPD have diffuse disease, minimal areas of lung hyperinflation, and most 
strikingly a reduction in alveoli and capillaries with little fibrosis.3,4 Premature infants with severe BPD 
are generally exposed to prolonged mechanical ventilation and oxygen-often for weeks to months. 
These infants have characteristic areas of hyperinflation alternated with areas of focal collapse, as well 
as hyperplasia of the bronchial epithelium.5,6 Radiography of these infants showed areas of 
heterogeneity throughout the lung fields and coarse scattered opacities in the most severe of infants.7 
Each year, approximately 17,500 premature infants in the U.S. and approximately 500 premature 
infants in Canada develop BPD each year. Although rare in the general population, BPD is the most 
common pulmonary morbidity associated with prematurity and is increasing. 
Approximately 50,000 infants in the U.S. and 1,500 infants in Canada are born each year at  
≤ 28 weeks gestational age, and ~35% of these infants develop BPD. The incidence of BPD varies 
widely between centers even after adjusting for potential risk factors. Data from 2010 from the Vermont 
Oxford Network shows the rates of BPD vary from 12% to 32%, depending on center, among infants 
born less than 32 weeks gestation. The rising number of infants with BPD might be due to the 
improvement in the survival of extremely low gestational age infants that leads to an increase in the 
numbers of preterm infants who survive with BPD.8,9 With increased survival of more very low birth 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
3 
CONFIDENTIAL 
 
weight infants, due to several pre-and post-natal interventions, the number of infants at risk for 
developing BPD is increasing.10 
BPD is associated with life-long problems. Premature infants with BPD have a longer initial 
hospitalization than their peers without BPD11 and BPD remains a substantial lifelong burden. 
Premature infants with severe BPD are particularly challenging for clinicians and frequently suffer from 
multiple morbidities such as pulmonary hypertension, prolonged hospitalization and death.12-14 The 
costs of the disorder are both social and economic and are measured in impaired childhood health and 
quality of life, family stress and economic hardship, and increased healthcare costs.15-17 
The strongest risk factor for BPD is prematurity. Epidemiologic studies of cohorts of premature 
infants consistently find that lower gestational age and lower birth weight are associated with an 
increased risk of BPD. 18,19 Rojas et al20 identified low birth weight and presence of a patent ductus 
arteriosus (PDA) as risk factors for BPD in premature infants between 500 and 1000 g. Marshall et al21 
identified gestational age, birth weight, nosocomial infection, fluid intake on day 2, PDA, and ventilation 
at 48 hours of life as risk factors for BPD. A secondary analysis of the Neonatal Research Network 
(NRN) Glutamine trial identified lower birth weight, lower gestational age, male sex, lower 1 and  
5-minute Apgar scores, higher oxygen requirement at 24 hours of age, longer duration of assisted 
ventilation, use of postnatal steroids for BPD, presence of severe intraventricular hemorrhage, proven 
necrotizing enterocolitis, PDA, and late onset sepsis as risk factors for BPD.22 In preterm infants with 
respiratory failure enrolled in the NRN Inhaled Nitric Oxide trial, the authors found that the risk of BPD 
was associated with lower birth weight, higher oxygen requirement, male sex, additional surfactant 
doses, higher oxygenation index and outborn status.23 Until recently, using these risk factors for 
prediction of BPD has been challenging. 
Accurate prediction of BPD risk is now possible: The NICHD NRN developed an online, publicly 
available BPD prediction tool (https://neonatal.rti.org or enter NICHD BPD estimator in a search engine) 
that accurately predicts the risk of developing BPD by postnatal day using only 7 readily available 
variables: postnatal day, gestational age, birth weight, sex, race/ethnicity, type of ventilator support, 
and FiO2 (%) (on the postnatal day of interest). Previous BPD prediction scoring systems have not 
been widely adopted, and each has had significant limitations. Some have satisfactory sensitivity and 
specificity but use a now outdated definition of BPD as oxygen therapy at 28 postnatal days.24-26 Some 
include radiographs as part of the scoring system, which introduces subjectivity and reduces 
generalizability. Other limits to the utility of these models are the inclusion of ventilated infants only, the 
lack of categorization of BPD by severity, the exclusion of infants who die, and under-utilization of 
antenatal corticosteroids and surfactant therapy.27-34 Most importantly, none examined models by 
postnatal day through the first 28 postnatal days. The prediction tool is internally and externally 
validated and the models classify infants in the internal validation sample into the correct level of BPD 
or death in more than 8 out of 10 cases. 
Recently, investigators identified risk factors for BPD, and the competing outcome of death, by postnatal 
day in 3,636 infants 23-30 weeks gestation at six postnatal ages (postnatal day 1, 3, 7, 14, 21, and 28) 
using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2.35 The 
investigators developed a web-based estimator using this clinical information to predict risk of BPD or 
death (https://neonatal.rti.org). BPD was defined as a categorical variable (none, mild, moderate, or 
severe). Using this estimator, typical risks of moderate to severe BPD or death are presented in 
Table 2-2. Based on data used to develop the BPD estimator, the cohort of infants meeting the 
inclusion criteria for this study are at high risk (generally >50 %) of developing moderate or severe BPD, 
or death. 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
4 
CONFIDENTIAL 
 
 
Table 2-2. Typical risk of moderate or severe BPD, or death, by postnatal day and respiratory 
support in premature infants 23-27 weeks gestation35 
Mechanical ventilation 
NCPAP or HFNC 
Postnatal day 
Postnatal day 
Gestational age (wks) 
7 
14 
21 
28 
7 
14 
21 
28 
23-27 weeks, % risk 
65-80 
71-77 
75-78 
81-83 
47-69 
55-65 
52-57 
60-64 
 
There are currently no therapies indicated by the U.S. FDA or Health Canada that prevent BPD or are 
available to treat BPD symptoms. To date, only vitamin A and caffeine prevent BPD without known 
significant long term adverse events.35-37 Postnatal steroids reduce BPD, but increase the risk of 
cerebral palsy.38,39 Although inhaled nitric oxide is beneficial in term infants with hypoxic respiratory 
failure, the majority of studies demonstrate that it does not prevent BPD in premature infants, although 
there was a great deal of heterogeneity in the patient populations, dose, and duration of inhaled nitric 
oxide.40 One problem with the vast majority of trials of drugs tested to prevent BPD is that they did not 
establish the safety, preliminary effectiveness, PK, pharmacodynamics, or dose prior to implementation 
of phase 3 randomized, controlled trials.41 
Sildenafil improves short term outcomes in children and adults with pulmonary hypertension. 
Sildenafil is a potent inhibitor of type 5 phosphodiesterase, the 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 (PAH). In pediatric patients 1 to 17 years old, sildenafil is approved by the FDA for the 
treatment of PAH (WHO Group I) to improve exercise ability and, in pediatric patients too young to 
perform standard exercise testing, pulmonary hemodynamics thought to underly improvements in 
exercise.42 The safety and effectiveness of sildenafil has not been established in pediatric patients 
younger than 1 year of age. Health Canada states sildenafil is not indicated in pediatric patients. The 
effect of sildenafil on premature infants at risk for BPD is unknown. 
Sildenafil reduces lung injury and preserves normal vasculature in preclinical models. BPD is 
characterized by lung injury, inflammation, abnormal alverolarization, and dysregulated vascular 
development. Preclinical models demonstrate that sildenafil might prevent ischemic-perfusion injury 
and improve lung function (rat43), suppress inflammatory mediators (mouse17,18; also, matrix 
metalloproteinase-2 in cell cultures44) that contribute to lung injury and BPD, and improve 
alveolarization and lung vascular development.17,18 Thus, sildenafil may prevent the development of 
BPD. 
Case reports suggest sildenafil improves outcomes in premature infants with BPD and 
pulmonary hypertension. Two case reports documented the successful resolution of pulmonary 
hypertension, measured by echocardiogram, in premature infants with BPD and pulmonary 
hypertension who were treated with sildenafil.45,46 In a small case series, enteral sildenafil at  
1.5-8 mg/kg/day in 22 premature infants with a median gestational age of 28 weeks  
(range 23-41 weeks) with lung disease (72% with BPD) resulted in improved hemodynamics 
determined by echocardiogram.47 A retrospective case series including 23 preterm infants with median 
gestational age of 26 weeks (interquartile range 23-29 weeks) treated with 1-7.3 mg/kg/day of oral 
sildenafil for BPD-associated pulmonary hypertension in a level 3 NICU found a significant 
improvement in pulmonary hypertension based on echocardiography in the majority (71%) of patients, 
with a minority (35%) of patients demonstrating a significant clinical response as defined by oxygen 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
5 
CONFIDENTIAL 
 
requirement and mean airway pressure.48 This report reflects the common clinical practice of using 
echocardiograms to follow premature infants with severe BPD and pulmonary hypertension. These 
reports do not establish the efficacy or safety of sildenafil in premature infants; more data is required 
from well-designed clinical trials. 
Sildenafil is increasingly being used off-label in premature infants. Data was examined from the 
Pediatrix Medical Group, a U.S. consortium of NICUs which encompasses 20% of all NICUs and 
~90,000 admissions/year. Sildenafil use increased exponentially from 2001-201049 (Figure 1). Infants 
exposed to sildenafil increased by >1000% (#2 among all drugs used in the NICU) from 2005-2010, 
from 0.2 to 2.3 per 1000 admissions. Sildenafil is increasingly being used in premature infants with little 
efficacy or safety data. 
Table 2-3. Top 5 % change drugs among 450,386 infants in 305 NICUs 
 
Rank 
 
Medication 
% 
Change 
Use 
(2005) * 
 
Use (2010) * 
1 
Azithromycin 
2900 
0.1 
3.0 
2 
Sildenafil 
1050 
0.2 
2.3 
3 
Milrinone 
900 
0.4 
4.0 
4 
Ibuprofen 
650 
1.4 
11 
5 
Carnitine 
517 
0.6 
3.7 
*Per 1000 infants 
Source: Pediatrix Medical Group 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
6 
CONFIDENTIAL 
 
Figure 2-1. Infants exposed to sildenafil in the Pediatrix Medical Group52 
 
Source: Pediatrix Medical Group 
 
Sildenafil pharmacokinetic and safety have not been adequately studied in premature infants. In 
adults, sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 
41%.50-52 Maximum observed plasma concentrations are reached within 30–120 minutes (median  
60 minutes) of oral dosing. In term infants with persistent pulmonary hypertension, sildenafil lowers 
mortality.53 Doses of up to 3 mg/kg/dose up to four times per day (12 mg/kg/day) have been reported in 
term infants.54 
 
Table 2-4. Adult, child, and infant clinical pharmacology parameters of sildenafil50-52,54,55 
Adult, FDA label 
Children, N=235 
Term, N=36 
Premature 
Postnatal Age 
N/A 
N/A 
<3 days 
Infants 
Volume of distribution 
105-140 L/70 kg 
150 L/70 kg 
456 L/70 kg 
Unknown 
Clearance 
31 L/hr/70 kg 
13.7L/hr/70 kg 
62 L/hr/70 kg 
Unknown 
Half-life 
3-4 hours 
4.7 hours 
48-56 hours 
Unknown 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
7 
CONFIDENTIAL 
 
The efficacy target is unknown, however, an AUC24 of 2650 ng*hr/mL (sildenafil plus the active 
metabolite) is equivalent to an oral adult dose of 20 mg three times daily, which decreases symptoms 
of pulmonary hypertension in adults.56 Efficacy and safety data from premature infants are lacking. 
The risks of “excessive” rates of administration of sildenafil are unknown. Studies of IV administration 
with higher rates of infusion (median dose – 0.35 mg/kg (range 0.125, 0.45 over 20 minutes: 5.5 times 
higher dose and 10 minute faster infusion time than the proposed study) in older children (median age 
3.3. years) were not associated with hypotension.57,58 One infant in the SIL01 study (see below) who 
received an IV dose of sildenafil at higher rate of infusion than specified in the protocol suffered from 
lower blood pressure. The SIL02 protocol uses intensive blood pressure monitoring, a lower starting 
dose of sildenafil, and a gradual dose escalation to the target dose to minimize the risk of high infusion 
rate associated low blood pressure. 
Investigators completed a pilot randomized study of enteral sildenafil in premature infants  
<28 weeks of gestation at risk of BPD and enrolled 20 participants: 10 received oral sildenafil  
3 mg/kg/day (mean gestational age 24 + 5 weeks (SD 4.9 days), mean weight 692 g (SD 98 g)) and  
10 received placebo (mean gestational age 24 + 5 weeks (SD 6.5 days), mean weight 668 g (SD 147 g)).59 
Short term respiratory parameters (duration of mechanical ventilation, duration of NCPAP) were not 
statistically significant between groups. (clinicaltrials.gov; NCT00431418). This study did not collect PK 
data. 
The Pediatric Trials Network conducted a Phase 1 study of sildenafil in premature infants with 
BPD (NICHD-2012-SIL01,IND 112,374,NCT01670136, Protocol Chair Matthew Laughon): The trial 
enrolled 25 premature infants ≤28 weeks gestational age (range 22-27 weeks) who were receiving 
sildenafil per local standard of care at doses between 0.5-2.25 mg/kg in cohort 1. The trial enrolled  
9 premature infants ≤ 28 weeks gestational age (range 23-27 weeks) and postnatal age range  
7-40 days who received a single intravenous dose of sildenafil 0.25 mg/kg or 0.125 mg/kg in cohort 2. 
Separate interim PK analyses were completed on samples from the 12 participants in Cohort 1 and 
samples from the 7 participants in Cohort 2. 
Cohort 1 (N=12): all subjects received drug PO, with 39 quantifiable PK samples collected for 
sildenafil and N-desmethyl sildenafil concentration. All subjects received at least 6 doses prior to PK 
sampling. 
Median (range) sildenafil and N-des-methyl sildenafil (DMS) concentrations were 60.4 ng/mL (4.7-369.4) 
and 46.9 ng/mL (5.6-275.2), respectively. The median DMS: sildenafil concentration ratio was 0.7 (0.2-4.7). 
Analysis of this preliminary data indicates that a one compartment body model best described the 
sildenafil PK data. Population estimates of CL/F and V/F, both scaled to a 70-kg adult weight, were 
50.7 L/h and 357 L, respectively (Table 2-5). 
Table 2-5. Parameter estimates for the base population PK model for sildenafil. 
Parameter 
Estimate 
RSE 
(%) 
Shrinkage 
(%) 
2.5th 
 %ile 
Bootstrap* 
Median 
97.5th 
%ile 
Structural Model 
-1 
KA (H ) 
2.4 FIXED 
- 
- 
- 
- 
- 
CL/F70KG (L/H) 
50.7 
14.1 
- 
37.6 
50.7 
68.6 
V/F70KG (L) 
357 
20.1 
- 
264.4 
357.9 
575.2 
Inter-Individual Variability (%CV) 
CL/F 
38.6 
52.1 
1.7 
15.2 
37.5 
55.9 
Residual error 
Proportional Error (%) 
41.7 
34.7 
9.5 
24.9 
40.2 
53.9 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
8 
CONFIDENTIAL 
 
*1,000 bootstrap runs were performed 
 
Assuming a bioavailability of 41%, a DMS: sildenafil area under the concentration versus time curve 
(AUC) ratio of 0.7 following oral administration, and that DMS has 50% the activity of the parent 
compound, individual estimates of CL/F and dose were used to predict steady-state AUC24,(SIL+DMS) for 
the 12 subjects in cohort 1. The median (range) predicted steady-state AUC24, (SIL+DMS) was  
1203 (502-3,480) ng*h/mL. If a 0.5 mg/kg intravenous dose is administered to 12 premature infants of 
the same weight, and assuming a 15% DMS: sildenafil AUC ratio following intravenous administration,9 
predicted steady-state AUC24,(SIL+DMS) would be 1335 (841-3,583) ng*h/mL. 
Cohort 2 (N=7): All subjects received sildenafil via intravenous administration at a dose of 0.25 mg/kg. 
A total of 26 PK samples were collected, 4 (15%) of which were scavenged samples. There was one 
sample (not scavenged) that was below the limit of quantification (BQL) for sildenafil, whereas there 
were no BQL samples for DMS. The median (range) number of samples collected per subject was  
3 (3-4). The median (range) dose was 0.251 mg/kg (0.247-0.254) or 0.180 mg (0.170-0.304). 
The median (range) sildenafil and DMS concentrations (not including scavenged samples) were  
25.40 ng/mL (0.28-193.07) and 2.84 ng/mL (0.21-17.95), respectively. The median DMS: sildenafil 
concentration ratio was 0.18 (0.0064-16.10). One infant experienced hypotension, which was deemed 
to be related to sildenafil. This subject had two PK samples collected and the sildenafil (0.29 ng/L and 
BQL) and DMS (0.87 and 4.67 ng/mL) concentrations were within the range of values observed for the 
other six subjects (median [range] sildenafil and DMS were 27.40 ng/mL [0.28-193.07] and 2.84 ng/mL 
[0.21-17.95], respectively). 
Following a single intravenous dose of 0.25 mg/kg, sildenafil exposures were within the range of 
estimates previously reported for infants following multiple oral dosing. Additional data collected in this 
study will provide the opportunity to perform a more robust PK analysis and provide meaningful 
estimates of sildenafil disposition in premature infants following both oral and intravenous 
administration. 
Adverse Events, Cohorts 1 and 2 (Table 2-6): All enrolled participants in cohorts 1 and 2 completed 
the study. In cohort 1, there were 13 adverse events with 1 serious adverse event occurring in  
1 participant. Eight of the 25 participants experienced at least one adverse event. The adverse events 
were not found to be related to the study drug. In cohort 2, there were 10 adverse events with 4 serious 
adverse events. Seven of the 9 participants experienced at least one adverse event and 4 of these 
experienced at least one serious adverse event. One of the 4 serious adverse events was found to be 
related to the study. The 1 related event was an episode of hypotension which was determined to be 
related to a faster than expected infusion rate. The event led to a Data Safety Monitoring Board 
(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 longer infusion 
time (30 minutes) and the dose was lowered by 50% to 0.125mg/kg. When the study re-opened  
2 additional subjects were enrolled without any related adverse events. 
 
 
 
 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
9 
CONFIDENTIAL 
 
 
 
Table 2-6. Summary of All Adverse Events in Phase 1 Study of Sildenafil
 
 
Determining the safety of sildenafil in premature infants is an urgent, unmet public health need. 
Investigating sildenafil addresses a research gap in neonatology because: 1) premature infants with 
BPD often die or have life-long problems; 2) there are no drugs that are FDA or Health Canada 
indicated for preventing BPD; and 3) sildenafil is commonly used off-label to treat or prevent BPD 
without adequate safety or efficacy data. 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
2.3.1.1 Risks of Blood Drawing 
There are small risks to blood sampling, usually some pain/discomfort with the blood stick and blood 
loss. Every effort will be made to avoid additional (to standard of care) sticks for this study and will time 
clinical blood draws to coincide with timed samples, using existing intravenous lines when possible. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
10 
CONFIDENTIAL 
 
2.3.1.2 
Sildenafil 
1. Per the FDA, the safety and effectiveness of sildenafil have not been established in pediatric 
patients younger than 1 year of age. Health Canada states sildenafil is not indicated in pediatric 
patients (< 18 years old).  
2. There is a theoretical risk of an increase in retinopathy of prematurity (ROP) that has been 
reported in a case report in the literature; this has been refuted by cohort studies.60 
3. Sildenafil has vasodilatory properties that can result in mild and transient decreases in blood 
pressure. See sildenafil package insert for additional information. 
4. The most common side effect observed in children is an erection that lasts for more than  
4 hours (priapism). See sildenafil package insert for additional information 
5. See also Section 2.2. (Table 2-6) Scientific Rationale Adverse Events, Cohorts 1 and 2 for AEs 
in study NICHD-2012-SIL01. 
Minimizing risk: We have minimized these risks by studying sildenafil in a different age group and a 
different disease state (premature infants at risk for BPD). We will review safety data prior to dose 
escalation between cohorts (see Section 10.3). Risks of retinopathy of prematurity have been 
minimized by administering sildenafil before the proliferative period of retinopathy of prematurity  
(32-34 weeks adjusted age). We will collect treatment of ROP as an outcome. 
2.3.2 
Potential Benefits 
Sildenafil may improve pulmonary mechanics, reduce exposure to mechanical ventilation, and prevent 
BPD. Although these improvements are not proven, increase in pulmonary function and decrease risk 
of BPD 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. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
11 
CONFIDENTIAL 
 
3. OBJECTIVES AND OUTCOME MEASURES 
3.1 
Objectives 
3.1.1 
Primary Objective 
Describe the safety of sildenafil in premature infants at risk of BPD. 
3.1.2 
Secondary Objective 
Preliminary effectiveness and pharmacokinetics (PK) of sildenafil. 
3.2 
Outcome Measures 
3.2.1 
Primary Outcome Measures 
Safety as determined by adverse events experienced by the participants. 
3.2.2 
Secondary Outcome Measures 
3.2.2.1 Preliminary effectiveness: Risk of BPD 
The outcome measure is a reduction in moderate-severe BPD or death risk from first day of study drug 
to end of study drug administration. Moderate-severe BPD or death risk will be defined by the NICHD 
NRN BPD outcome estimator (https://neonatal.rti.org/). 
The BPD outcome estimator uses the following information to provide individual risk of BPD: 
1. Gestational age (weeks) 
2. Birth weight (g) 
3. Sex 
4. Maternal Race/Ethnicity (White/Hispanic/Black) 
5. Postnatal day (1, 3, 7, 14, 21, 28) 
6. Ventilation type (on the postnatal day of interest: HFvent, IMV/SIMV, CPAP, Cannula/hood 
or none) 
7. FiO2 (%) (on the postnatal day of interest) 
Note: The NICHD NRN BPD estimator provides an estimate of the risk of BPD (as defined by NIH: 
none, mild, moderate, severe) or death by postnatal day. The risk of BPD is presented as a 
percentage. For this protocol, we will dichotomize the outcome as above (none-mild vs. 
moderate-severe-death). 
Risk of BPD or death as defined by the NICHD NRN BPD estimator will be collected on days 7, 14,  
21 and 28 of study drug period. The BPD estimator rate will be calculated using the day closest to the 
participant’s postnatal age. The BPD estimator includes infants up to 28 postnatal days; for infants  
>28 postnatal days, the 28 day estimates will be used. 
3.2.2.2 Pharmacokinetics 
A population PK analysis will be performed. Using the final population PK model, empirical Bayesian 
estimates of clearance (CL), volume of distribution (V), half-life, and exposure metrics (e.g. AUC, 
maximum concentration) will be generated for each participant. 
3.2.3 
Other Safety and Efficacy Outcomes 
1. Death: All infants who died at or before 36 weeks PMA will be included. 
2. BPD: BPD is defined as using a method modified from the NICHD NRN BPD estimator. We will 
define BPD as a dichotomous (none-mild vs. moderate-severe- death) variable and as a 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
12 
CONFIDENTIAL 
 
categorical variable (none/mild, moderate, severe or death)among survivors by modifying the 
NIH consensus definition of BPD20, 21 to include infants transferred prior to 36 weeks and the 
need for oxygen at 36 weeks PMA (or discharge, if sooner than 36 weeks PMA).29 For the 
purpose of this study we will define BPD as follows: 
No/Mild BPD: participant is not receiving supplemental O2 at 36 weeks PMA 
Moderate BPD: participant is receiving O2 supplementation >21% but <30% at  
36 weeks PMA, but not receiving positive pressure at 36 weeks PMA. 
Severe BPD: participant is receiving O2 supplementation ≥30% and/or positive pressure 
at 36 weeks PMA. 
3. Death or BPD (moderate or severe) 
4. ROP: Retinopathy (retinopathy of prematurity) will be defined as treatment for ROP (laser 
photocoagulation, cryotherapy, or intraocular injections, such as bevacizumab). 
5. Pulmonary hypertension: Pulmonary hypertension will be defined as present or not 
present per echocardiogram and/or cardiac catheterization reports, as provided per 
standard of care. Echocardiogram and cardiac catheterization reports will be reviewed 
centrally by a single Duke pediatric cardiologist. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
13 
CONFIDENTIAL 
 
4. STUDY DESIGN 
Multi-center, randomized, placebo-controlled, sequential cohort dose escalating, double masked, safety 
study. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
14 
CONFIDENTIAL 
 
5. STUDY POPULATION 
5.1 
Selection of the Study Population 
Premature infants (inpatient in neonatal intensive care units) will be randomized in a dose escalating 
approach 3:1 (sildenafil: placebo) sequentially, into each of three cohorts. There will be approximately 
40 randomized and dosed participants in each cohort for a total of up to 120 participants. 
5.2 
Inclusion/Exclusion Criteria 
5.2.1 
Inclusion Criteria 
1. Documented informed consent from parent or guardian, prior to study procedures 
2. Receiving positive airway pressure (nasal continuous airway pressure, nasal intermittent 
positive pressure ventilation, or nasal cannula flow > 1LPM) or mechanical ventilation (high 
frequency or conventional) at time of randomization* 
3. < 29 weeks gestational age at birth 
4. 7-28 (inclusive) days postnatal age at time of randomization* 
5.2.2 
Exclusion Criteria 
1. Previous enrollment and dosing in NICHD-2015-SIL02 “Safety of Sildenafil in Premature 
Infants at Risk of Bronchopulmonary Dysplasia” 
2. Previous exposure to sildenafil within 7 days prior to randomization* 
3. Currently receiving vasopressors* 
4. Currently receiving inhaled nitric oxide* 
5. Baseline mean arterial pressure < gestational age (in weeks) plus postnatal age (in weeks) 
within 24 hours of randomization*; e.g. an infant at 25 weeks gestational age and 3 weeks 
postnatal age with MAP <28 mm Hg would be ineligible 
6. Known allergy to sildenafil 
7. Known sickle cell disease 
8. AST > 225 U/L < 72 hours prior to randomization* 
9. ALT > 150 U/L < 72 hours prior to randomization* 
10. Any condition which would make the participant, in the opinion of the investigator, 
unsuitable for the study* 
* Participant will be re-assessed prior to dosing to reconfirm eligibility criteria if >24 hours elapse between randomization 
and first study dose. 
5.3 
Treatment Assignment Procedures 
5.3.1 
Additional Participants 
If a participant is randomized (Section 5.3.2) and receives < 7 days of study drug, then additional 
participants may be enrolled. 
5.3.2 
Randomization Procedures 
Participants who satisfy all eligibility criteria will be randomized 3:1 (sildenafil: placebo). All three 
cohorts will use the same randomization scheme. The participant’s randomized treatment assignment 
will be obtained through the Advantage eClinical® enrollment module. In the event that Advantage 
eClinical® is not available at the time of randomization, a back-up system specified in the Manual of 
Procedures (MOP) will be used. If a participant is randomized but does not receive study drug, that 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
15 
CONFIDENTIAL 
 
participant will not count towards total sample size and will be replaced by a new participant who, in 
turn, will be assigned a new identification number and receive treatment corresponding to the new 
identification number. The reason for not dosing the participant will be noted on the electronic case 
report form (CRF). The randomization process will not determine if an IV or enteral dose is used. 
Investigators are encouraged to use intravenous dosing if the patient has IV access. Participants 
should not have an IV placed specifically for study drug administration alone. However, if a site deems 
that a second IV would optimize the safe administration of other medications or fluids while 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. 
5.3.3 
Masking Procedures 
Infants randomized to the placebo treatment group will receive the equivalent volume of dextrose 5% 
appropriate for IV use or enteral use (if receiving enteral study drug). The pharmacy at each site will 
prepare and dispense the study drug into appropriate sized syringes in a masked manner (e.g. amber 
syringe), staff accessing participant outcomes will be masked to treatment. 
5.3.4 
Reasons for Participant Withdrawal 
The site investigator may choose to suspend study drug dosing for up to 48 hours for any reason. If 
study drug is suspended for >48 hours, the study drug administration will be stopped and the 
participant will proceed directly into the safety follow-up period (and will have all remaining 
assessments collected). If study drug is suspended for >48 hours for a documented safety concern, the 
suspension will not be considered a protocol deviation. 
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: 
1. During the course of the study, the participant fits safety-related criteria for which they 
would have been excluded from the study in the first place (ALT > 150 U/L, AST > 225 U/L, 
or infant started on vasopressor or inhaled nitric oxide (Section 5.2). 
2. Any clinically significant adverse event (e.g. hypotension) that is deemed by the site 
investigator to require discontinuation of study drug (Section 8.1.4 for definition of 
hypotension.) 
3. A participant develops hypotension during the study drug infusion. 
4. Unmasking of the participant treatment is performed. All unmasking events should be 
recorded on a protocol deviation form in electronic data capture (EDC) system within  
24 hours of the unmasking. The decision to unmask will be made in consultation with 
the Medical Monitor if possible. 
5. Requested by the NIH, FDA, PTN, Health Canada or DSMB. 
Before discontinuing a participant from the study drug, the local investigator must contact the medical 
monitor or Study PI except in emergency situations. Participants who are prematurely discontinued 
from the study drug for any reason will be followed for 28 days for safety monitoring, and will have  
36 weeks PMA and final study assessments collected. 
The participant’s parent or guardian may withdraw voluntarily from participation in the study at any time. 
The participant’s parent or guardian is not obligated to state the reason for withdrawal. The reasons for 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
16 
CONFIDENTIAL 
 
withdrawal, or failure to provide a reason, must be documented by the investigator on the 
completion/withdrawal section of the corresponding CRF. Participants/guardians who withdraw consent 
will not have any additional data entered in the EDC system. 
5.3.5 
Termination of Study 
This study may be terminated at any time by FDA, NIH, Health Canada, the Investigational New Drug 
Application (IND) or Clinical Trial Application (CTA) sponsor, or the Data Safety Monitoring Board 
(DSMB). If the study is terminated, notification to FDA and U.S. investigators will be made in 
accordance with 21 CFR 312.56(d) and Health Canada and Canadian investigators will be made in 
accordance with Canadian Food and Drug Regulation C.05.015. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
17 
CONFIDENTIAL 
 
6. STUDY PROCEDURES 
6.1 
Summary of Procedures 
Table 6-1. Schedule of study procedures 
 
 
Screen/ 
Baseline Treatment 
Weaning9 
Cohort 2 and 3 
Follow-up 
SAE 
Follow-up 
36 weeks 
PMA 
assessment6 
Final study 
assessment 
Time (Day) 
Pre-
dose1 
1-287 
(± 1 Day) 
Weaning 
Day 1-6 
Day 1-14 post 
last study dose11 
Day 15-28 
post last study 
dose11 
36 weeks 
PMA 
(+ 6 days) 
Discharge or 
Transfer 
Informed 
consent 
X 
Demographics10 
X 
Physical 
examination 
X 
X (WEEKLY) 
X 
X 
Medical history 
X 
Actual Weight 
X 
X 
(WEEKLY) 
X (WEEKLY) 
X 
X 
Mean Arterial 
Pressure 
X 
X 
LAST DAY OF 
WEAN 
X (WEEKLY) 
Respiratory 
assessment 
X 
X 
(WEEKLY) 
LAST DAY OF 
WEAN 
X (WEEKLY) 
X 
X 
Laboratory 
evaluations2 
X 
X 
(WEEKLY) 
X (WEEKLY) 
X 
Study drug 
administration 
X4 
X 
Concomitant 
medications 
X 
X 
Adverse Events 
(including 
SAEs) 
X5 
X 
X 
X 
SAEs Only 
X 
Echocardiogram 
and Cardiac 
catheterization 
reports8 
X 
X 
X 
X 
X 
X 
PK sampling 
X (AFTER 
DAY 7) 
Discharge 
information, 
including ROP3 
X 
1 Refers to <24 hours prior to start of study drug that these procedures (except labs) 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. 
2If not performed per standard of care (SOC), labs must be taken within 72 hrs. prior to randomization and weekly (at any time) during 
treatment; weekly during the first 14 days of the follow-up period. 
3Transfer, discharge, duration of hospitalization or death; record results of ROP, if treatment required. 
4 Dosing may be adjusted according to any weight changes determined at baseline, study days 7, 14, and 21. 
5 AEs will be collected following initial study-specific procedure (e.g., screening blood draws, dosing) 
6Assessment must occur between 36 weeks 0 days PMA to 36 weeks 6 days PMA. 
7Collect all safety follow-up and remaining assessments if early withdrawal of study drug occurs during the 28 day treatment period. 
8 If performed per local standard of care. 
9Weaning 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. 
10Maternal race/ethnicity will be collected. 
11 Includes weaning during cohort 2 and 3. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
18 
CONFIDENTIAL 
 
6.2 
Screen/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 CRF from the clinical medical record: 
1. Participant demographics, including birth weight and gestational age at birth 
2. Maternal Race/Ethnicity (White/Hispanic/Black) 
3. Medical history 
4. Physical examination, including actual weight 
5. MAP A. Obtained at screening/baseline. All mean arterial pressure (MAP) values obtained 
24 hours before the first dose 
6. Concomitant medications (within 24 hours prior to start of study drug) 
7. Respiratory assessment (Section 6.8) 
8. Laboratory evaluations (Section 6.9) 
9. Echocardiogram and Cardiac catheterization reports, if performed per local standard of 
care 
10. Adverse events following initial study-specific procedure (Section 6.11) 
6.3 
Treatment Period 
The treatment period will include days 1-28 or last day of study drug if early withdrawal of study drug. 
The following information will be collected and recorded while the participant is on study drug: 
1. Actual weight on study days 7 (+/- 1 day), 14 (+/- 1 day), 21 (+/- 1 day), and 28 (+/- 1 day) 
of study drug administration 
2. Date, time, amount and route of study drug dose 
3. All concomitant medications 
4. MAP 
A. All mean arterial pressure (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: 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
19 
CONFIDENTIAL 
 
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 (one hour), then 
hourly (+/- 15 minutes) for 4 hours, then and 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, weekly (Section 6.8) 
6. Laboratory evaluations, at least once a week (Section 6.9). 
7. Echocardiogram and Cardiac catheterization reports, if performed per local standard of 
care 
8. PK sampling (after Day 7 – Section 6.10) 
9. Adverse events (Section 6.11) 
6.4 
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. Adverse events (Section 6.11) 
3. MAP (the lowest valid MAP value on last day of wean should be recorded). 
4. Respiratory assessment on last day of wean (Section 6.8) 
5. Echocardiogram and Cardiac catheterization reports, if performed per local standard of 
care 
6.5 
Follow-up Period 
Follow-up period will include days 1-28 after last study dose, last study 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 EDC at Day 7 and 14 of the follow-up period (or 
day closest to and after Day 7 and 14, if >1 assessment is available), except for SAEs (which will be 
reported from days 1-28): 
1. Physical examination, including actual weight 
2. MAP (the lowest valid MAP value on Day 7 and Day 14 should be recorded) 
3. Respiratory assessment (Section 6.8) 
4. Laboratory evaluations (Section 6.9) 
5. Echocardiogram and Cardiac catheterization reports, if performed per local standard of 
care 
6. Adverse events (only during follow-up period days 1-14 – Section 6.11) 
7. Serious adverse events (during follow-up period days 1-28 – Section 6.11) 
6.6 
36-week PMA Assessment 
The following information will be reported at 36 weeks (+ 6 days) PMA if available. If the participant is 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
20 
CONFIDENTIAL 
 
discharged before 36 weeks, record assessment closest to discharge date. If more than one 36-week 
assessment is available record results obtained closest to Week 36, 0 days: 
1. Physical examination, including actual weight 
2. Respiratory assessment (Section 6.8) 
3. Laboratory evaluations (Section 6.9) 
4. Echocardiogram and Cardiac catheterization reports, if performed per local standard of 
care 
6.7 
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 6.8) 
3. Echocardiogram and Cardiac catheterization reports, if performed per local standard of 
care 
4. Discharge information 
A. Discharge or transfer 
B. Death 
C. Duration of hospitalization 
5. Record results of ROP, if treatment required 
6.8 
Respiratory Assessment 
The following information will be collected at baseline, on day 7 (+/- 1 day), 14 (+/- 1 day), 21  
(+/- 1 day), and 28 (+/- 1 day) of initial study drug administration, once during the weaning period, twice 
during the follow-up period, once at 36 weeks PMA, and once at discharge (if applicable): Maximum 
blended O2 (blended O2 for each assessment 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.) 
1. Ventilation type: 
A. High frequency ventilator 
B. Conventional mechanical ventilator 
C. NCPAP (or equivalent, see inclusion criteria in protocol synopsis table) 
D. Cannula/Hood 
E. None (room air with no support) 
F. Other: presence of Tracheostomy or Extracorporeal Membrane Oxygenation 
(ECMO) 
6.9 
Laboratory Evaluations 
The following laboratory evaluations must be conducted (if not obtained per standard of care [SOC]) 
within 72 hours prior to randomization, and at least once per week during the treatment and weekly 
during the first 14 days of the follow-up period (at any time during the week). The lab values will also 
be recorded at 36 weeks PMA if available. 
1. AST 
2. ALT 
If the above laboratory evaluations are obtained more frequently than required by protocol, all test 
results must be entered into the EDC system. SOC laboratory evaluations: We will also record all 
values for platelets, phosphorus, chloride, alkaline phosphatase, and caffeine levels within 72 hours 
prior to randomization through 14 days following the last dose of study drug (include weaning doses). 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
21 
CONFIDENTIAL 
 
6.10 PK Sampling 
Table 6-2 below provides the optimal PK sampling collection windows. Blood samples will be collected 
after any dose following completion of 7 days (168 hours) of study drug administration. 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; 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 6-2. Target PK Sampling Times (time in relation to end of infusion and flush) 
Intravenous or enteral per clinical care 
Time* 
PK # 
Enteral** 
Intravenous** 
1 
0 – 15 min 
0 – 15 min 
2 
30 – 60 min 
30 – 60 min 
3 
1 – 2 hr 
1 – 2 hr 
4 
2 – 3 hr 
2 – 3 hr 
5 
3 – 4 hr 
3 – 4 hr 
6 
4 – 5 hr 
4 – 5 hr 
7 
15 min prior to next dose 
15 min prior to next dose 
8^ 
(elimination) 
16 – 24 hr 
16 – 24 hr 
* Time starts at end of flush which must be less than or equal to 30 minutes. 
** May be drawn around more than one dose. 
**Sample is taken after dose of study drug (and flush if given by IV). 
^ Sample taken 16-24 hrs. after last dose. 
6.10.1 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 collected. 
Cohort 1 and 2 Infants assigned to the sildenafil treatment group in cohorts 1 and 2, will only have PK 
analysis conducted. 
Infants assigned to the placebo treatment group in cohorts 1 and 2, will only have biomarkers of 
bronchopulmonary dysplasia measured in a central laboratory (details in MOP; biomarkers may 
include: BNP, IL-1, IL-6, IL-8, TNF-α) instead of PK levels. 
Cohort 3 All infants in cohort 3 (placebo and active arm) will have biomarkers of bronchopulmonary 
dysplasia measured in a central laboratory (details in MOP; biomarkers may include: NT-proBNP, 
MR-proANP, in addition to BNP, IL-1, IL-6, IL-8, TNF-α). Only infants assigned to the active treatment 
group will have PK levels assessed. 
 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
22 
CONFIDENTIAL 
 
6.10.2 Specimen Preparation, Handling, and Shipping 
Detailed information will be in the MOP. 
6.11 Adverse Event 
AEs will only be collected following initial study-specific procedure (e.g., screening blood draws, drug 
administration), through 14 days post last study dose (which includes weaning doses). SAEs will be 
collected following initial study-specific procedure (e.g., screening blood draws, drug administration), 
through 28 days post last study dose (which includes weaning doses). Refer to Section 6 for safety 
information. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
23 
CONFIDENTIAL 
 
7. STUDY DRUG DESCRIPTION 
7.1 
Dosage and Study Drug Information 
In the U.S., sildenafil, in both intravenous (IV) and for oral suspension, has been approved for use in 
other populations and for other indications by the FDA. For the indication of PAH in adults, the oral 
dose is 20 mg three times a day or 10 mg three times a day if administered as an intravenous bolus 
injection. In pediatric patients (ages 1-17), the approved recommended oral dosing is 10 mg three 
times a day (<20 kg), 20 mg three times a day (20-45 kg), 20 mg three times a day (>45 kg). In 
pediatric patients >45 kg, doses may be increased up to 40 mg three times a day based on symptoms 
and tolerability.42 
In Canada, only the intravenous and tablet formulation have marketing approval, and sildenafil is not 
approved for use in pediatric patients < 18 years old. Pfizer Inc. and Mylan Inc., a Viatris Inc. company 
will provide the oral suspension (enteral) formulation to U.S. and Canadian sites. In Canada, the 
enteral formulation will be provided to Canadian sites as investigational product under a CTA. 
Study dosing and escalation is described in Table 7-2. Refer to Section 7.3 for study drug packaging 
and labeling. 
Table 7-1. Treatment Period Dosing 
Table. N and dosing scheme 
N 
Sildenafil 
(IV) 
Sildenafil 
(enteral) 
N 
Cohort N 
Cohort 1 
Placebo 
10 
0.125 mg/kg 
q 8 hours 
0.25 mg/kg 
q 8 hours 
30 
40 
Cohort 2 
Placebo 
10 
0.5 mg/kg 
q 8 hours 
1 mg/kg 
q 8 hours 
30 
40 
Cohort 3 
Placebo 
10 
1 mg/kg 
q 8 hours 
2 mg/kg 
q 8 hours 
30 
40 
 
Dosing escalation: Participants in Cohort 1 will start at 0.0625 mg/kg IV (or 0.125 mg/kg enteral) 
every 8 hours and the dose will increase to 0.125 mg/kg IV (or 0.25 mg/kg enteral) after 6 doses  
(48 hours). Participants enrolled in Cohort 2 and Cohort 3 will initially start at 0.125 mg/kg IV  
(or 0.25 mg/kg enteral) every 8 hours and the dose will increase by 0.125 mg/kg IV (or 0.25 mg/kg 
enteral) to the target dose every 6 doses. This means that the dose will increase every 48 hours. 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. Infants 
who do not initially qualify for escalation should be reevaluated daily for whether they meet these 
criteria, and escalation must occur within 24 hours of an infant meeting all criteria (respiratory and 
laboratory). If escalation does not occur within this timeframe, then a protocol deviation must be 
recorded. 
Note: DSMB safety review (Section 10.3) is required prior to enrolling to next cohort. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
24 
CONFIDENTIAL 
 
Table 7-2. Dosing escalations for each sequential cohort 
Cohort 1 
Cohort 2 
Cohort 3 
Day 
# 
Dose 
# 
IV 
(mg/kg) 
Enteral 
(mg/kg) 
IV 
(mg/kg) 
Enteral 
(mg/kg) 
IV 
(mg/kg) 
Enteral 
(mg/kg) 
1-2 
1-6 
0.0625 
0.125 
0.125 
0.25 
0.125 
0.25 
3-4 
7-12 
0.125 
0.25 
0.25 
0.5 
0.25 
0.5 
5-6 
13-18 
0.125 
0.25 
0.375 
0.75 
0.375 
0.75 
7-8 
19-24 
0.125 
0.25 
0.5 
1 
0.5 
1 
9-10 
25-30 
0.125 
0.25 
0.5 
1 
0.625 
1.25 
11-12 
31-36 
0.125 
0.25 
0.5 
1 
0.75 
1.5 
13-14 
37-42 
0.125 
0.25 
0.5 
1 
0.875 
1.75 
15 + 
43 + 
0.125 
0.25 
0.5 
1 
1 
2 
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 weekly check (within 7 days) prior and closest 
to dose increase. 
7.1.1 
Adjusting dose for weight: 
The actual weight should be reviewed weekly (plus or minus one day, Section 6.4) and the dose of the 
study drug may be adjusted. DSMB safety review (Section 10.3) is required prior to enrolling to next 
cohort. 
7.2 
Weaning Period Schedule: 
Sildenafil is commonly used at higher doses to treat pulmonary hypertension 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 
BPD, target doses in cohorts 2 and 3 are similar to those used for the treatment of pulmonary 
hypertension. 
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 participant is 
withdrawn from the study. Wean by 25% of last study dose every 2 days until off. Participants will 
complete the wean after 6 days. 
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 
 
Weaning is not required for participants in Cohort 1 as the risk of rebound effects is likely minimal for 
infants receiving sildenafil at these low doses. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
25 
CONFIDENTIAL 
 
Weaning for a withdrawn participant: If a participant in cohort 2 or 3, escalates to a dose of ≥0.5 mg/kg 
IV (or ≥1mg/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. 
7.3 
Formulation, Packaging, and Labeling 
IV 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. 
Enteral Formulation: U.S. commercially available REVATIO sildenafil citrate powder for suspension 
(Manufactured by: Fareva Amboise) will be distributed for use to all sites and labeled in accordance 
with 21 CFR 312.6. 
Any requisite clinical trial materials will be provided with labeling in accordance with all applicable 
regulatory requirements. Detailed information regarding formulation, packaging and labeling will be 
included in the MOP. 
For Canada, enteral drug product will be labeled for investigational use in accordance with Health 
Canada regulations (C.05.011), prior to shipment to Canadian sites under a CTA. 
7.4 
Preparation and Administration of Study Intervention/Study Drug 
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. The investigational pharmacist will be unmasked and will prepare 
masked study drug. Detailed information will be included in the MOP. If the participant experiences 
signs or symptoms deemed by the investigator to be clinically significant hypotension or other type of 
SAR, the infusion will be stopped. Resumption of 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. 
7.5 
Product Storage and Stability 
All investigational products 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 investigational 
product-specific requirements provided by the Sponsor. 
Detailed information on handling storing and reconstitution is found in the Package Insert. 
7.6 
Concomitant Medications/Treatments 
All drug and/or treatments are permitted while on study. All concomitant medications and treatments 
will be reported within 24 hours prior to the start of study drug and during the 28-day treatment 
administration period. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
26 
CONFIDENTIAL 
 
8. ASSESSMENT OF SAFETY 
8.1 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
Safety will be assessed following initial study-specific procedure e.g., screening blood draws, dosing 
through 14 days post last study dose (last study dose includes weaning doses) and it will be assessed 
by frequency and incidence of AEs and SAEs. A safety monitoring committee (DSMB) will be convened 
by NIH to review data and safety information from study participants throughout the study and prior to 
opening of cohorts 2 and 3 (see Sections 8.4 and 10.3). 
Monitoring for SAEs will continue for a total of 28 days post last study drug dose (including the weaning 
doses). 
8.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not considered 
drug-related, which occurs during the conduct of a clinical trial. (Any change in clinical status, routine 
labs, x-rays, physical examinations, etc.), that is considered clinically significant by the study 
investigator is considered an AE. 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. A reasonable possibility implies that there is evidence that the drug 
caused the event. 
Adverse reaction is any adverse event caused by the drug. 
Serious adverse event or serious suspected adverse reaction or serious adverse reaction as 
determined by the investigator, or the sponsor is any event that results in any of the following 
outcomes: 
1. Death 
2. Life-threatening AE (“life-threatening” means that the study participant was, in the opinion 
of the investigator or sponsor, at immediate risk of death from the reaction as it occurred 
and required immediate intervention) 
3. Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
4. Inpatient hospitalization or prolongation of existing hospitalization 
5. Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention to 
prevent one of the outcomes listed in the above definition of serious event 
6. Confirmed cases of Hy’s Law 
8.1.2 
Unexpected Adverse Event or Reaction 
This is defined as any adverse event not listed in the package insert or investigational brochure or 
investigational plan or is not listed at the specificity or severity in the package insert or investigational 
brochure or investigational plan. 
8.1.3 
Identification of Events and Timeframe for Reporting 
As all participants in this study will have pre-existing medical conditions and may be currently 
hospitalized, those pre-existing conditions will not be considered as adverse events. New events that 
occur or pre-existing conditions that worsen in terms of frequency or intensity will be reported as 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
27 
CONFIDENTIAL 
 
adverse events. 
All reportable events as defined above, determined to be an AE based on physical examination, 
laboratory findings, or other means, will be reported in the electronic case report form (e-CRF). The 
investigator will provide the date of onset and resolution, intensity, frequency, action(s) taken, changes 
in study drug dosing, relationship to study drug, and outcome. 
8.1.4 
Low Blood Pressure and Hypotension 
Blood pressure will be determined using mean arterial pressure (MAP). For each participant, MAPs will 
be taken as noted in Section 6.4. MAP will be measured using an appropriate size cuff or with an 
intra-arterial placed catheter that measures continuous blood pressure. 
8.1.5 
Primary Definition of Hypotension 
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. 
8.1.6 
Presumed low blood pressure and presumed hypotension 
Presumed low blood pressure will be considered as one valid MAP (in mmHg): 
• 
< gestational age at birth (in weeks) plus postnatal age (in weeks) in mmHg 
• 
< gestational age at birth (in weeks) in mmHg 
• 
< 30 mmHg 
• 
During times of intensive MAP recording (Section 6.3), one valid MAP of >30% lower than 
baseline. Baseline MAP is the mean of the 3 valid MAPs prior to the first dose or dose 
escalation (i.e. the mean of the following 3 MAPs: 2 hours [+/- 5 minutes],  
1 hour [+/- 5 minutes], and 15 minutes [+/- 5 minutes]). 
Presumed hypotension will be defined as 2 valid MAPs (in mmHg), taken 15-60 minutes apart: 
• 
< gestational age at birth (in weeks) plus postnatal age (in weeks) in mmHg 
• 
< gestational age at birth (in weeks) in mmHg 
• 
< 30 mmHg 
• 
During times of intensive MAP recording (Section 6.3), two valid MAPs of >30% lower than 
baseline. Baseline MAP is the mean of the 3 MAPs prior to the first dose or dose escalation 
(i.e. the mean of the following 3 valid MAPs: 2 hours [+/- 5 minutes], 1 hour [+/- 5 minutes], 
and 15 minutes [+/- 5 minutes]). 
If an infant has presumed hypotension as defined above i.e. < gestational age at birth (in weeks) plus 
postnatal age (in weeks) in mmHg that is not considered a suspected adverse reaction, then that event 
will be flagged by the EDC system and will be reviewed by the Study Team for possible DSMB review. 
8.1.7 
Follow-up of Adverse Events 
All events (study-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. 
All serious suspected adverse reactions and severe adverse events will be followed until resolution or 
until the patient is medically stable. Any adverse event beginning more than 14 days after the last dose 
of study drug and any serious adverse event beginning more than 28 days after the last dose of study 
drug will not be captured. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
28 
CONFIDENTIAL 
 
In cases when the baby 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 to contact the participant/guardian. 
8.1.8 
Guidelines for Assessing Intensity of an Adverse Event 
The investigator should use the following definitions when assessing intensity of an adverse 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 to require intervention 
3. SEVERE: Participant experiences symptoms or findings that require significant intervention 
8.1.9 
Guidelines for Determining Causality 
The investigator will use the following question when assessing causality of an adverse event to study 
drug, where an affirmative answer designates the event as a suspected adverse reaction: 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. 
8.1.10 
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 
an AE, whether serious or non-serious, must be followed by the investigator until the clinical outcome 
from the AE is determined. Any participant who experiences an AE may be withdrawn at any time from 
the study at the discretion of the investigator. The AE(s) should be noted on the appropriate CRFs, 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. 
8.1.11 
Investigator Reporting Procedures 
Serious events will be entered into the data system immediately and no later than within 24 hours of 
identification. Non-serious adverse events will be entered into the safety data system within 7 days of 
identification. If there are any technical difficulties, the SAE will be reported by direct communication 
with the medical monitor. 
8.2 
Serious Adverse Events 
Any serious adverse event entered in the safety database will generate an automatic email notification 
to the IND sponsor or the in-country designee and funding sponsor. The DCC medical monitor will 
review all SAEs at the time that they are reported. Investigators must also submit safety reports locally 
as required by their IRB/REB. 
8.3 
Regulatory Reporting 
Any event that requires reporting to Regulatory Authorities (i.e. Serious Unexpected Suspected 
Adverse Reactions or SUSARS) based on applicable national regulations will be forwarded to the 
sponsor in time to meet reporting requirements, (e.g. 7 days for fatal and life-threatening (expedited) 
initial reports, with follow up reports within another 8 days, 15 days for all other SUSARs). The sponsor 
or the in-country representative will submit safety reports (e.g. IND safety reports) to the regulatory 
agencies as necessary and will inform the investigators of such regulatory reports. Site investigators 
must submit safety reports as required by their IRB/REB. Documentation of the submission and receipt 
by the IRB/REB must be retained for each expedited safety report. 
All serious events irrespective of their designation as “related” or “not related” to study drug(s) will be 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
29 
CONFIDENTIAL 
 
reported to the FDA at least annually in a summary format. 
8.4 
Safety Oversight 
The DSMB will review serious adverse events on a monthly basis. In addition, a qualified and 
experienced clinician not otherwise associated with this protocol will serve as the medical monitor. The 
medical monitor will review all 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. 
The medical monitor will also indicate whether he/she concurs with the details of the report provided by 
the study investigator. If no SAEs prompt review at an earlier time point, the DSMB will review AEs and 
SAEs at the regularly scheduled meeting. Additionally, DSMB will periodically review interim safety 
analyses (Section 10.3). The DSMB will convene and make recommendations on termination of the 
study based on review of safety reports and halting rules. The safety data will be compiled by DCC. 
Based on the recommendations of the DSMB, and NIH, the IND sponsor will make a decision to 
terminate or continue the study. 
8.5 
Halting Criteria: Safety Concerns 
An unscheduled DSMB review of safety data will be triggered if: (a) ≥3 patients in a cohort have 
treatment completely stopped due to the same AE with a causal relationship to study treatment, or (b) if 
≥3 patients in a cohort have the same SAE, or (c) ≥3 patients in a cohort have a Serious Adverse 
Reaction. Enrollment will be suspended during DMC review, though study activities will be allowed to 
proceed on previously enrolled subjects if applicable. If there are 3 or more Serious Adverse Reactions 
in a cohort, then we will also inform the NICHD, FDA and Health Canada, and the DSMB may choose 
to be unmasked to treatment assignment. The DSMB may receive unmasked safety data if safety 
concerns are identified at any point during the study. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
30 
CONFIDENTIAL 
 
9. CLINICAL MONITORING 
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 DCRI sponsor standard operating procedures. The IND/CTA 
sponsor, or as detailed in the Transfer of Regulatory Obligations (TORO), the BPCA DCC, NIH, or its 
designee will conduct site-monitoring visits as detailed in the monitoring plan or in the Manual of 
Procedures (MOP). 
Site visits will be conducted at standard intervals as defined by the site monitoring plans and may be 
made more frequently as directed by the IND sponsor. Monitoring visits will include, but are not limited 
to, review of regulatory files, accountability records, CRFs, informed consent forms, medical and 
laboratory reports, and protocol compliance. Study monitors will meet with investigators to discuss any 
problems and actions to be taken and document visit findings and discussions. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
31 
CONFIDENTIAL 
 
10. 
STATISTICAL CONSIDERATIONS 
10.1 Study Endpoints 
Primary safety endpoints are the incidence of AEs and SAEs. Secondary endpoints include change in 
BPD risk, BPD incidence, death rate, incidence of death or BPD, incidence of ROP, and incidence of 
pulmonary hypertension. 
10.2 Sample Size Considerations 
The sample size of 30 in each dose group is sufficient to estimate AE or SAE incidence with sufficient 
precision. Table 10-1 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. An event with an 
incidence rate of 0.05 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 10-1. 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 
 
Population for Analysis 
All participants enrolled, randomized, and dosed will be included in the safety population and the safety 
analyses. All participants who had at least one interpretable PK sample will be included in the PK 
analysis. 
10.3 Interim Safety Analysis 
The DSMB must complete a review of the safety data after completion of each cohort prior to opening 
enrollment into the next cohort. For cohort 1, this review was initiated once the 14 day follow up period 
post treatment for the last participant was completed. For cohort 2, the DSMB will review safety data 
once the 28 day follow up period post treatment is completed for the 36th participant. Approval for 
opening cohort 3 to enrollment will begin only after the DMC has completed their review of these safety 
data up to, and including, the 36th participant, and provided a recommendation that the study proceed 
with enrollment to the next cohort. Enrollment of the remaining four participants in cohort 2 will continue 
while the DSMB review of the safety data is ongoing. Cohort 3 enrollment will not begin until cohort 2 is 
closed. The remaining safety data among the last four participants will be reported to the DSMB for 
review per the current study process (see Section 8.4). 
The DSMB will continue to review the safety report on participants at regular DSMB meetings that 
occur two to three times a year. The number and percent of AEs and SAEs within each dose group will 
be summarized overall as well as by each Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term. Laboratory data will be tabulated by dose groups. 
Summary statistics for changes from baseline will be presented. 
See Section 8.5 for additional details for halting criteria for safety concerns. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
32 
CONFIDENTIAL 
 
10.4 Analysis Plan 
Analyses will be presented by treatment groups. There are 4 planned treatment groups: 1) participants 
randomized to sildenafil in Cohort 1; 2) participants randomized to sildenafil in Cohort 2; 3) participants 
randomized to sildenafil in Cohort 3 and 4) participants randomized to placebo. 
10.4.1 Descriptive statistics 
Descriptive statistics such as number of observations, mean, median, standard deviation, standard 
error, 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.) 
10.4.2 Demographic and baseline characteristics 
The number of participants completed and discontinued early from study and the reasons for the 
discontinuation will be summarized by treatment group. Demographic and baseline characteristics will 
also be summarized by treatment group. Variables include race, age, sex, and selected clinical 
variables recorded prior to initiation of study drug. Study drug administration will be summarized in 
terms of route, number of days of dosing and reasons for final discontinuation of study drug. 
10.4.3 Safety 
The primary safety endpoint is number and percent of AEs and SAEs and will be summarized by 
treatment groups. AEs and SAEs will be presented overall and by each Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred term. Prior and concomitant 
medications will be summarized by World Health Organization (WHO) drug class. Laboratory data will 
be tabulated by treatment groups. Summary statistics for changes from baseline will be presented. 
Hypotension, presumed hypotension and presumed low blood pressure (as defined in Section 8.1.4) will 
be summarized by treatment group. 
10.4.4 Effectiveness analysis 
Multivariable mixed-effects model will be used to explore the relationship between the maximum and 
total dose of sildenafil and change in the risk of moderate BPD, severe BPD or death at 7, 14, 21 and 
28 days of study drug. A dose by time interaction term will allow us to estimated change in the risk of 
BPD within each treatment group and make comparisons between treatment groups. 
Death, BPD status, death or moderate/severe BPD, ROP, and pulmonary hypertension will be 
evaluated at 36 weeks PMA using logistic regression analyses to evaluate the effect of dose. 
Adjustments will be made for important covariates such as GA, birth weight, sex and maternal 
race/ethnicity. 
10.4.5 PK analysis plan 
PK parameters will be estimated by population PK approach using non-linear mixed effects modeling in 
NONMEM. The influence of covariates on PK parameters will be explored. 
10.4.6 Biomarkers 
We will relate the concentration of biomarkers (Section 6.10.1) to the development of and severity of 
BPD. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
33 
CONFIDENTIAL 
 
11. 
PARTICIPANT CONFIDENTIALITY 
Participant confidentiality is held strictly in trust by the participating investigators, their staff, and the 
sponsor(s) 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 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. 
This study is covered by a Certificate of Confidentiality (CoC) from the NIH. The CoC prevents U.S. 
courts and other U.S. agencies from forcing the study team to share information that may identify the 
participants during a legal or legislative action unless the participant allows this. The CoC does not 
keep the participants from sharing information about their participation in this study. 
For Canadian participants, the NIH CoC may protect data housed in the United States from legal 
proceedings, but disclosure may still occur if required by Federal, State, or local laws, which may be 
different from Canadian law. Canadian federal and provincial regulations will govern the confidentiality 
of data maintained at the Canadian sites. 
After the study is completed, information about the study, including study data, will be submitted to the 
NIH data repository (https://dash.nichd.nih.gov; referred to below as “DASH” (Data and Specimen 
Hub). With NIH approval, the data submitted to DASH may be used by other researchers for future 
research. The study data submitted to DASH will be de-identified. When de-identified study data are 
provided to other researchers for the purposes of future research, it may be done without obtaining 
additional permission from the participant. Canadian participants must consent to this arrangement 
before their data is provided. 
The principal investigator will ensure that the use and disclosure of personal health information 
obtained during this research study complies with the Federal Privacy Regulations. 
For Canadian sites, privacy requirements are described in several Federal and Provincial laws and 
regulations. Examples include, but are not limited to the Federal Personal Information Protection and 
Electronic Documents Act, Genetic Non-Discrimination Act, the Ontario Personal Health Information 
Protection Act, Quebec’s Act Respecting the Protection of Personal Information in the Private Sector, 
the BC Personal Information Protection Act, Alberta’s Personal Information Protection Act and Health 
Information Act. Note that for several provinces more than one act may apply. 
In the U.S., the Health Insurance and Portability and Accountability (HIPAA) Privacy Rule applies. The 
rule provides U.S. federal protection for the privacy of protected health information sent to or collected 
in the U.S. 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 Canadian Federal and Provincial 
laws or the HIPAA Privacy rule, whichever applies. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
34 
CONFIDENTIAL 
 
12. 
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. Permission forms will be IRB/REB-approved, and 
the IRBs/REBs will determine whether one parent or both parents must provide permission. 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. For non-English speakers, a fully translated 
permission document or an oral presentation accompanied by a short form may be used to obtain 
informed permission. The fully translated permission document and the short form must be approved 
by the IRB/REB and executed according to IRB/REB requirements. 
The IND/CTA sponsor or designee will provide the investigator, in writing, any new information that 
bears significantly on the participants' risk to receive the study drug. This new information will be 
communicated by the investigator to participants' parents/legal guardians/LARs in accordance with 
IRB/REB requirements. The informed permission document will be updated, and, if necessary, the 
informed permission process will be repeated and participants’ parents/legal guardians/LARs asked to 
sign updated permission documents. 
Site staff may employ IRB/REB-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. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
35 
CONFIDENTIAL 
 
13. 
FUTURE USE OF SPECIMENS 
Biological samples collected as part of this study may be shipped periodically to the PTN central 
laboratory(s) for protocol defined testing (e.g., drug concentration measurements of PK samples). 
After the study is completed, all leftover 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/REB 
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 information of the 
participant. With NIH approval, the de-identified study samples may be made available to other 
researchers. 
Parents/legal guardians/LARs are asked to provide informed consent/permission for the biological 
sample collection process, specimens repository, and potential for future research prior to the child’s 
participation in the study. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
36 
CONFIDENTIAL 
 
14. SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
An electronic case report form (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 investigator(s) 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/REB 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 ICH E6 (R2), Section 4.9, 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, which include, but are not limited to, hospital records, clinical and office charts, laboratory 
notes, memoranda, 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, and participant files and records kept at the pharmacy, 
at the laboratories, and medico-technical departments involved in the clinical trial. Case report forms 
will be derived from the eCRF and provided by the Data Coordinating Center (DCC). 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
37 
CONFIDENTIAL 
 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The principal investigator will provide direct access to all trial-related sites, source data/documents, 
case report forms, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. The principal investigator will 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, Good Clinical Practice, and the applicable 
regulatory requirements. Clinical monitoring reports will be submitted to the PI, and NIH. 
The DCC 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. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
38 
CONFIDENTIAL 
 
16. 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
16.1 Ethical Standard 
The investigator will ensure that the study will be conducted in accordance with the protocol, the ethical 
principles of Good Clinical Practice (ICH E6 (R2)) that have their origin in the Declaration of Helsinki, 
and all applicable national and local regulations. The investigator will ensure that the study is 
conducted in accordance with the provisions as stated and will comply with the prevailing local laws 
and customs. 
16.2 Institutional Review Board/Research Ethics Board 
Prior to enrollment of participants into this trial, the protocol, the parental permission form, and any 
materials or advertisements presented to participants or potential participants, will be reviewed and 
approved by the appropriate IRB/REB. 
The responsible official for the IRB/REB will sign the letter of approval of the protocol prior to the start 
of this trial, and a copy will be provided by the site study team to the DCC. Notification of the IRB/REB's 
composition and the institution’s federal-wide assurance number (if applicable) will be provided to the 
DCC. 
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/REB. 
Any refusals by IRBS/REBS must be documented for reporting to Heath Canada. 
16.3 Informed Consent 
The investigator will choose participants in accordance with the eligibility criteria detailed previously. To 
prevent bias, the investigator will not exercise selectivity. Since it is not possible to obtain participant 
consent or assent in this study, parents/legal guardians/legally authorized representatives (LARs) will 
provide informed permission for study participation. 
Before any study procedures or treatments are administered, all parents/legal guardians/LARs must 
provide informed permission, and sign a permission form that complies with the federal requirements 
and an authorization form that complies with federal and provincial privacy regulations for the use and 
disclosure of the participant’s protected health information. The permission form and the authorization 
form must be approved by the DCC and by the IRB/REB. 
For details regarding the informed permission process, see Section 12. 
The study monitor or other authorized representatives of the sponsor may inspect all documents and 
records required to be maintained by the investigator. This documentation includes, but is not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
Clinical study sites will permit access to such records. 
16.4 Study Discontinuation 
If the study is discontinued, enrolled participants will continue to be followed for safety assessments for 
28 days. All adverse events must be followed through resolution. Notification to regulatory authorities, 
REBs and participants will be carried as required by regulation (e.g. U.S. 21 CFR 312.56, Canadian 
FDR C.05.012, C.05.015). 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
39 
CONFIDENTIAL 
 
17. 
DATA HANDLING AND RECORD KEEPING 
U.S. investigators are obligated to conduct this study in accordance with U.S. Federal Regulation  
21 CFR 312.60-69 as specified on the signed form FDA 1572, applicable local laws, and the 
International Conference on Harmonisation: Good Clinical Practice: Consolidation Guideline. 
Canadian investigators must conduct the study in accordance with Canadian Food and Drug 
Regulations Part C Division 5, and in particular the undertakings and practices described in: 
C.05.012(3)(f) (Qualified Investigator Undertaking) and C.05.010 concerning Good Clinical Practices. 
The investigator is responsible for informing the IRB/REB of any safety issues related to the study and 
the study drug, including reports of serious adverse events, 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 or reported. 
Case report forms will be derived from the eCRF and provided by the DCC to the sites to record and 
maintain data for each participant enrolled in the study. All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data. Permanent ink is required to data 
integrity and ensure clarity of reproduced copies. When making a change or correction, the original 
entry should be crossed out with a single line, and the change should be initialed and dated. Do not 
erase, overwrite, or use correction fluid or tape on the original. 
Data reported in the eCRF should be consistent with the case report form/source documents, or the 
discrepancies should be documented. The sponsor and/or its designee will provide guidance to 
investigators on making corrections to the case report forms and eCRF. 
17.1 Data Management Responsibilities 
All case report forms 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 principal investigator or designee. Data collection is the 
responsibility of the clinical trial staff at the site under the supervision of the site principal investigator. 
During the study, the investigator must maintain complete and accurate documentation for the study. 
The DCC for this study will be responsible for data management, quality review, analysis, and reporting 
of the study data. 
17.2 Data Capture Methods 
Clinical data (including AEs 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 the case report 
forms/source documents. 
17.3 Timing/Reports 
The DSMB will convene and make recommendations on study continuation based on the safety data 
collected periodically. 
17.4 Study Records Retention 
Unless the Sponsor notifies the investigator otherwise, records and source documents pertaining to the 
conduct of the study, are to be retained by Investigators in the United States for a period of at least 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
40 
CONFIDENTIAL 
 
2 years after the date upon which the Sponsor’s application to the U.S. FDA is accepted, rejected or 
withdrawn, or in accordance with institutional requirements, whichever is longer. The disposition date of 
the Sponsor’s FDA application will be posted on the PTN website for the Investigators’ reference. In 
Canada study records will be retained for 25 years after the end of the study. 
17.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of procedures 
requirements. 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. 
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 
Internet Data Entry System (IDES). 
All deviations from the protocol must be addressed in study case report forms. A completed copy of 
the protocol deviation form must be maintained in the regulatory file. Protocol deviations must be 
submitted to the local IRB/IEC per their guidelines. The site PI/study staff is responsible for knowing 
and adhering to their IRB requirements. 
17.6 Participant Privacy/Authorization 
The principal investigator will ensure that the use and disclosure of protected/personal health 
information obtained during a research study complies with all privacy regulations. For Canadian sites, 
these requirements are described in several Federal and Provincial laws and regulations (for example 
the Federal Personal Information Protection and Electronic Documents Act, Genetic 
Nondiscrimination- Act, the Ontario Personal Health Information Protection Act, Quebec’s Act 
Respecting the Protection of Personal Information in the Private Sector, the BC Personal Information 
Protection Act, Alberta’s Personal Information Protection Act and Health Information Act). 
In the U.S., the HIPAA Privacy Rule applies. The HIPAA Privacy Rule applies to all PHI sent or 
collected in the U.S. for purposes of this research and provides U.S. federal protection for the privacy 
of protected health information 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 Canadian Federal & 
Provincial laws and regulations or the HIPAA Privacy Rule whichever applies. Authorization will be 
combined in the informed consent document (approved by the IRB/REB).  

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
41 
CONFIDENTIAL 
 
18. 
PUBLICATION POLICY 
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal under the oversight of the Publication Committee of the Pediatric Trials Network 
(PTN). The PTN Publication Committee comprises representatives of the network cores, 
thought-leaders, DCC, and PTN, and is responsible for generation and coordination of the publications 
that report scientific findings of the network. 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, DCC, and PTN that use PTN data are intended to 
represent the sponsor or the PTN 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 PTN 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 biomedical journals are considering adopting similar policies. It is 
the responsibility of the IND holder to register this trial in an acceptable registry. 
The ICMJE defines a clinical trial as any research project that prospectively assigns human participants 
to intervention or comparison groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. Studies designed for other purposes, such as to study 
pharmacokinetics or major toxicity (e.g., phase 1 trials), would be exempt from this policy. 
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. The NIH Public Access Policy ensures the public has access to the published results of 
NIH-funded research. It requires investigators to submit final peer-reviewed journal manuscripts that 
arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. Further, 
the policy stipulates that these papers must be accessible to the public on PubMed Central no later 
than 12 months after publication. Refer to: http://publicaccess.nih.gov/ and 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
42 
CONFIDENTIAL 
 
19. 
LITERATURE REFERENCES 
1. 
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American journal of respiratory and 
critical care medicine. 2001;163(7):1723-1729. 
2. 
Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Institutes of Health 
consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116(6):1353-1360. 
3. 
Coalson JJ, Winter V, deLemos RA. Decreased alveolarization in baboon survivors with 
bronchopulmonary dysplasia. American Journal of Respiratory & Critical Care Medicine. 
1995;152(2):640-646. 
4. 
Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 1999;46(6):641-643. 
5. 
Northway WH, Rosan RC, Porter DY. Pulmonary Disease Following Respirator Therapy of 
Hyaline-Membrane Disease. New England Journal of Medicine. 1967;276(7):357-368. 
6. 
Bancalari E. Barotrauma to the lung. In: A M, ed. Advances in Perinatal Medicine. New 
York: Plenum; 1982. 
7. 
Bancalari E, Gerhardt T. Bronchopulmonary dysplasia. Pediatric clinics of North 
America.1986;33(1):1-23. 
8. 
Stoelhorst GM, Rijken M, Martens SE, et al. Changes in neonatology: comparison of two 
cohorts of very preterm infants (gestational age <32 weeks): the Project On Preterm and 
Small for Gestational Age Infants 1983 and the Leiden Follow-Up Project on Prematurity 
1996-1997. Pediatrics. 2005;115(2):396-405. 
9. 
Hintz SR, Poole WK, Wright LL, et al. Changes in mortality and morbidities among infants 
born at less than 25 weeks during the post-surfactant era. Arch Dis Child Fetal Neonatal 
Ed. 2005;90(2):F128-133. 
10. 
Wadhawan R, Vohr BR, Fanaroff AA, et al. Does labor influence neonatal and 
neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by 
cesarean delivery? American journal of obstetrics and gynecology. 2003;189(2):501-506. 
11. 
Michael Cotten C, Oh W, McDonald S, et al. Prolonged hospital stay for extremely 
premature infants: risk factors, center differences, and the impact of mortality on selecting a 
best-performing center. J Perinatol. 2005;25(10):650-655. 
12. 
Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and functional outcomes of 
extremely low birth weight infants in the National Institute of Child Health and Human 
Development Neonatal Research Network, 1993-1994. Pediatrics. 2000;105(6):1216-1226. 
13. 
Wood NS, Costeloe K, Gibson AT, Hennessy EM, Marlow N, Wilkinson AR. The EPICure 
study: associations and antecedents of neurological and developmental disability at  
30 months of age following extremely preterm birth. Arch Dis Child Fetal Neonatal Ed. 
2005;90(2):F134-140. 
14. 
Fily A, Pierrat V, Delporte V, Breart G, Truffert P. Factors associated with 
neurodevelopmental outcome at 2 years after very preterm birth: the population-based 
Nord-Pas-de-Calais EPIPAGE cohort. Pediatrics. 2006;117(2):357-366. 
15. 
Katz-Salamon M, Gerner EM, Jonsson B, Lagercrantz H. Early motor and mental 
development in very preterm infants with chronic lung disease. Arch Dis Child Fetal 
Neonatal Ed. 2000;83(1):F1-6. 
16. 
McAleese KA, Knapp MA, Rhodes TT. Financial and emotional cost of bronchopulmonary 
dysplasia. Clinical pediatrics. 1993;32(7):393-400. 
17. 
Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thébaud B. Sildenafil improves 
alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury. American 
journal of respiratory and critical care medicine. 2005;172(6):750-756. 
18. 
de Visser YP, Walther FJ, Laghmani EH, Boersma H, van der Laarse A, Wagenaar GT. 
Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
43 
CONFIDENTIAL 
 
ventricular hypertrophy in neonatal hyperoxic lung injury. Respir Res. 2009;10(1):30-30. 
19. 
Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute 
of Child health and human development neonatal research network, January 1995 through 
December 1996. NICHD Neonatal Research Network. Pediatrics. 2001;107(1):E1. 
20. 
Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole C, Silva-Neto G. Changing trends in 
the epidemiology and pathogenesis of neonatal chronic lung disease. The Journal of 
pediatrics. 1995;126(4):605-610. 
21. 
Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O'Shea TM. Risk factors for 
chronic lung disease in the surfactant era: a North Carolina population-based study of very 
low birth weight infants. North Carolina Neonatologists Association. Pediatrics. 
1999;104(6):1345-1350. 
22. 
Oh W, Poindexter BB, Perritt R, et al. Association between fluid intake and weight loss 
during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low 
birth weight infants. The Journal of pediatrics. 2005;147(6):786-790. 
23. 
Ambalavanan N, Van Meurs KP, Perritt R, et al. Predictors of death or bronchopulmonary 
dysplasia in preterm infants with respiratory failure. J Perinatol. 2008;28(6):420-426. 
24. 
Ryan SW, Nycyk J, Shaw BN. Prediction of chronic neonatal lung disease on day 4 of life. 
European journal of pediatrics. 1996;155(8):668-671. 
25. 
Subhedar NV, Hamdan AH, Ryan SW, Shaw NJ. Pulmonary artery pressure: early 
predictor of chronic lung disease in preterm infants. Arch Dis Child Fetal Neonatal Ed. 
1998;78(1):F20-24. 
26. 
Romagnoli C, Zecca E, Tortorolo L, Vento G, Tortorolo G. A scoring system to predict the 
evolution of respiratory distress syndrome into chronic lung disease in preterm infants. 
Intensive care medicine. 1998;24(5):476-480. 
27. 
Toce SS, Farrell PM, Leavitt LA, Samuels DP, Edwards DK. Clinical and roentgenographic 
scoring systems for assessing bronchopulmonary dysplasia. American journal of diseases 
of children (1960). 1984;138(6):581-585. 
28. 
Corcoran JD, Patterson CC, Thomas PS, Halliday HL. Reduction in the risk of 
bronchopulmonary dysplasia from 1980-1990: results of a multivariate logistic regression 
analysis. European journal of pediatrics. 1993;152(8):677-681. 
29. 
Noack G, Mortensson W, Robertson B, Nilsson R. Correlations between radiological and 
cytological findings in early development of bronchopulmonary dysplasia. European journal 
of pediatrics. 1993;152(12):1024-1029. 
30. 
Yuksel B, Greenough A, Karani J. Prediction of chronic lung disease from the chest 
radiograph appearance at seven days of age. Acta Paediatr. 1993;82(11):944-947. 
31. 
Bhutani VK, Abbasi S. Relative likelihood of bronchopulmonary dysplasia based on 
pulmonary mechanics measured in preterm neonates during the first week of life. The 
Journal of pediatrics. 1992;120(4 Pt 1):605-613. 
32. 
Kim YD, Kim EA, Kim KS, Pi SY, Kang W. Scoring method for early prediction of neonatal 
chronic lung disease using modified respiratory parameters. Journal of Korean medical 
science. 2005;20(3):397-401. 
33. 
Sinkin RA, Cox C, Phelps DL. Predicting risk for bronchopulmonary dysplasia: selection 
criteria for clinical trials. Pediatrics. 1990;86(5):728-736. 
34. 
Rozycki HJ, Narla L. Early versus late identification of infants at high risk of developing 
moderate to severe bronchopulmonary dysplasia. Pediatric pulmonology. 
1996;21(6):345-352. 
35. 
Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short and 
long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev. 
2007(4):CD000501. 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
44 
CONFIDENTIAL 
 
36. 
Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. The New 
England journal of medicine. 2006;354(20):2112-2121. 
37. 
Laughon MM, Langer JC, Bose CL, et al. Prediction of bronchopulmonary dysplasia by 
postnatal age in extremely premature infants. American journal of respiratory and critical 
care medicine. 2011;183(12):1715-1722. 
38. 
McCormick A, Suguihara C, Huang J, et al. Depressed ventilatory response to hypoxia in 
hypothermic newborn piglets: role of glutamate. Journal of Applied Physiology. 
1998;84(3):830-836. 
39. 
Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for 
preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 
2010(1):Cd001146. 
40. 
Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm 
infants. Cochrane Database of Systematic Reviews. 2017(1). 
41. 
KN S SA, PB S, Laughon M. Review of randomized controlled trials for the prevention of 
bronchopulmonary dysplasia. ePAS. 2013:1547.1651. 
42. 
www.dailymed.nlm.gov. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=13390. Accessed 
February 10, 2023. . 
43. 
Liu Z, Fang L. Phosphodiesterase-5 inhibitor and rat lung ischemia-reperfusion injury. Asian 
Cardiovascular and Thoracic Annals. 2012;20(1):42-47. 
44. 
Sun XZ, Li ZF, Liu Y, Fang P, Li MX. Inhibition of cGMP phosphodiesterase 5 suppresses 
matrix metalloproteinase-2 production in pulmonary artery smooth muscles cells. Clin Exp 
Pharmacol Physiol. 2010;37(3):362-367. 
45. 
Caputo S, Furcolo G, Rabuano R, et al. Severe pulmonary arterial hypertension in a very 
premature baby with bronchopulmonary dysplasia: normalization with long-term sildenafil. 
Journal of Cardiovascular Medicine. 2010;11(9):704-706. 
46. 
Hon KL, Cheung KL, Siu KL, et al. Oral sildenafil for treatment of severe pulmonary 
hypertension in an infant. Biol Neonate. 2005;88(2):109-112. 
47. 
Mourani PM, Sontag MK, Ivy DD, Abman SH. Effects of long-term sildenafil treatment for 
pulmonary hypertension in infants with chronic lung disease. The Journal of pediatrics. 
2009;154(3):379-384, 384.e371-372. 
48. 
Trottier-Boucher MN, Lapointe A, Malo J, et al. Sildenafil for the Treatment of Pulmonary 
Arterial Hypertension in Infants with Bronchopulmonary Dysplasia. Pediatr Cardiol. 
2015;36(6):1255-1260. 
49. 
Perez KM CK, Herring AH, et al. Sildenafil exposure in the neonatal intensive care unit. ePAS. 
2012:1553.1559. 
50. 
Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and metabolism of sildenafil in 
mouse, rat, rabbit, dog and man. Xenobiotica; the fate of foreign compounds in biological 
systems. 1999;29(3):297-310. 
51. 
Muirhead GJ, Rance DJ, Walker DK, Wastall P. Comparative human pharmacokinetics and 
metabolism of single-dose oral and intravenous sildenafil. British journal of clinical 
pharmacology. 2002;53 Suppl 1:13S-20S. 
52. 
Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral 
doses in healthy male subjects: absolute bioavailability, food effects and dose 
proportionality. British journal of clinical pharmacology. 2002;53 Suppl 1:5S-12S. 
53. 
Vargas-Origel A, Gómez-Rodríguez G, Aldana-Valenzuela C, Vela-Huerta MM, 
Alarcón-Santos SB, Amador-Licona N. The use of sildenafil in persistent pulmonary 
hypertension of the newborn. Am J Perinatol. 2010;27(3):225-230. 
54. 
Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of 

NICHD-2015-SIL02 – SILDENAFIL  
 
 
 
 
 
 
 
      Version 7.0 
IND # 112374 
 
 
 
 
 
 
 
 
 
    
      03APR2023 
 
45 
CONFIDENTIAL 
 
neonates with persistent pulmonary hypertension. The Journal of pediatrics. 
2009;155(6):841-847.e841. 
55. 
Watt S, Nahashi N, Harnisch L, Gao X. Population pharmacokinetics (PK) of sildenafil in 
paediatric and adult patients with pulmonary arterial hypertension. ESC; August 
28- September 1, 2010, 2010; Stockholm, Sweden. 
56. 
Ahsman MJ, Witjes BC, Wildschut ED, et al. Sildenafil exposure in neonates with 
pulmonary hypertension after administration via a nasogastric tube. Arch Dis Child Fetal 
Neonatal Ed. 2010;95(2):F109-114. 
57. 
Hill KD, Tunks RD, Barker PCA, et al. Sildenafil exposure and hemodynamic effect after 
stage II single-ventricle surgery. Pediatr Crit Care Med. 2013;14(6):593-600. 
58. 
Tunks RD, Barker PC, Benjamin DK, Jr., et al. Sildenafil exposure and hemodynamic effect 
after Fontan surgery. Pediatr Crit Care Med. 2014;15(1):28-34. 
59. 
König K, Barfield CP, Guy KJ, Drew SM, Andersen CC. The effect of sildenafil on evolving 
bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot 
study. J Matern Fetal Neonatal Med. 2014;27(5):439-444. 
60. 
Fang AY, Guy KJ, König K. The effect of sildenafil on retinopathy of prematurity in very 
preterm infants. J Perinatol. 2013;33(3):218-221.