Sustained Aeration of Infant Lungs Trial
Phase: NA
Conditions: Preterm Birth, Extreme Prematurity
Sponsor: University of Pennsylvania

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The Sustained Aeration of 
Infant Lungs (SAIL) Study 
Protocol 
 
 
Sponsor 
Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
NIH Grant Number 
1-U01-HD072906-01A1 
Protocol Number 
Penn IRB# 819208 
Clinical Trials.gov Number 
NCT 02139800 
Version Number & Date 
Version 2.7  
March 15, 2017 
 

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Protocol Summary  
Study Title   
The Sustained Aeration of Infant Lungs (SAIL) Study 
Sponsor 
National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
Population 
Preterm infants born between 23-26 weeks gestational age  
Primary Objective 
To determine in preterm infants needing respiratory support at birth, which of 
two lung opening strategies – either a standard positive-end expiratory 
pressure /continuous positive airway pressure (PEEP/CPAP) of 5-7 cm H2O in 
the delivery room as compared to early lung recruitment using Sustained 
Inflation (SI) in the delivery room, will result in a lower rate of the combined 
endpoint of death or bronchopulmonary dysplasia (BPD) at 36 weeks 
gestational age 
Design and Sample 
Size  
This prospective multi-national randomized controlled trial (RCT) is a two-arm 
parallel design of two alternative courses of treatment.   
600 preterm infants – 300 control / 300 intervention  
Inclusion Criteria 
Infants who are born in participating NICUs (which do not use prophylactic 
surfactant) and who fulfill the following inclusion criteria are eligible for 
enrollment: (a) Gestational age (GA) at least 23 weeks but less than 27 
completed weeks by best obstetrical estimate; (b) requiring 
resuscitation/respiratory intervention at birth – “apneic, labored breathing, 
gasping” (as defined in NRP 2011 AAP 6th Edition p. 45.) 
Outcomes and 
Analytic Approach 
The primary outcome to be used for efficacy evaluation is rate of death or BPD 
at 36 weeks gestation age. Analysis of the primary outcome will be intention-
to-treat comparisons between treatment arms.  
Secondary outcomes include clinical measures collected from the first 10 days 
of life as well as neurodevelopment and respiratory outcomes at 22-26 months 
of corrected age in survivors.  Secondary outcomes will be analyzed using 
similar procedures to the primary outcome comparisons between treatment 
arms.  
Interim Analysis 
2 interim analyses conducted when 1/3 and 2/3 participants complete primary 
outcome. An additional SAE safety analysis after 100 subjects complete.  
Clinical Centers  
21 multi-national sites (USA, Canada, Italy, Germany, Netherlands, Australia, 
Austria, Singapore, S. Korea)  
Enrollment Period 
2.5 years 
Study Duration 
5 years 
ClinicalTrials.Gov 
Trial Link 
Registration Number 
Registration Title 
http://www.ClinicalTrials.gov 
NCT 02139800 
www.sailtrial.org  
The Sustained Aeration of Infant Lungs (SAIL) Study 

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Modifications Made in Protocol Version 2.7 dated 20170315 
 
 
Modification: Page 6: The version on the Investigator Agreement Page was changed to Version 
2.7_20170315. 
Modification: Page 14: The SAIL research network diagram was modified to reflect the addition of 7 
new sites – Christiana Care, Wake Med Health, Loma Linda University, KK Women’s and Children’s 
Hospital, Mater Mother’s Hospital, Seoul National University, and Samsung Medical Center.  
 
Modification: Page 15: The list of participating centers in Section 3.2 was modified to include the site 
names and site investigators. 

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LIST OF ABBREVIATIONS 
AAP 
American Academy of Pediatrics 
ACS 
Antenatal Corticosteroids 
AE 
Adverse events 
ANCS 
Antenatal Corticosteroid 
BAC 
Biostatistics Analysis Center 
BPD 
Bronchopulmonary Dysplasia 
BPM 
Beats per minute 
BSID 
Bayley Scale of Infant Development 
BW 
Birth weight 
CAP 
Caffeine for Apnea of Prematurity trial 
CCC 
Clinical Coordinating Center 
cGA 
Corrected Gestational Age 
COI 
Conflicts of Interest 
COIN 
Continuous Positive Airway Pressure or Intubation at Birth Trial  
CP 
Cerebral palsy 
CPAP 
Continuous positive airway pressure 
CRF 
Case Report Form 
CRCU 
Clinical Research Computing Unit 
CXR 
Chest x-ray 
DCC 
Data Coordinating Center 
DR 
Delivery room 
DSMC 
Data Safety Monitoring Committee 
ELGAN 
Extremely Low Gestational Age Newborns 
ENaCs 
Epithelial Sodium Channels 
FiO2 
Fraction of inspired oxygen 
FRC 
Functional Residual Capacity 
FWA 
Federal Wide Assurance 
GA 
Gestational age 
GEE 
Generalized estimating equation 
GMFCS 
Gross Motor Function Classification System 
HR 
Heart rate 
HUP 
Hospital of the University of Pennsylvania 
IC 
Informed consent 
IDE 
Investigational Device Exemption 
ILCOR 
International Liaison Committee on Resuscitation 
IND 
Investigational New Drug 
IPPV 
Intermittent positive pressure ventilation 
IRB 
Institutional review board 
IT 
Information technology 
IQR 
Interquartile range 
IVH 
Intraventricular hemorrhage 

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MAP 
Mean airway pressure 
MRI 
Magnetic resonance imaging 
MR SOPA 
Mask, readjustment, suction airway, open mouth, increase pressure, alternative airway 
nCPAP 
Nasal continuous positive airway pressure 
NDI 
Neurodevelopmental impairment 
NICHD 
(Eunice Kennedy Shriver) National Institute of Child Health and Human Development 
NICU 
Neonatal intensive-care unit 
NIH 
National Institute of Health 
NRP 
Newborn (or Neonatal) Resuscitation Program 
OHRP 
Office for Human Research Protections 
ORT 
Oxygen Reduction Test 
PaO2 
Partial pressure of oxygen in blood 
PCO2 
Carbon Dioxide partial pressure 
PDA 
Patent ductus arteriosus 
PEEP 
Positive end-expiratory pressure 
PIE 
Pulmonary interstitial emphysema 
PINT 
The Premature Infants in Need of Transfusion Study 
PIP 
Peak inspiratory pressure 
PMA 
Postmenstrual age 
PPV 
Positive pressure ventilation 
RCT 
Randomized controlled trial 
RDS 
Respiratory distress syndrome  
ROP 
Retinopathy of prematurity 
RT 
Respiratory therapist 
SAE 
Serious Adverse Events 
SAIL 
Sustained Aeration of Infant Lungs 
SD 
Standard deviation 
SGA 
Small for gestational age 
SI 
Sustained inflation 
SNAPPE 
Score for Neonatal Acute Physiology Perinatal Extension 
SpO2 
Blood oxygen saturation  
SUPPORT 
Surfactant, Positive Pressure, and Oxygenation Randomized Trial 
TIPP 
Trial of Indomethacin Prophylaxis in Preterm Infants 
UAC 
Umbilical artery catheter 
UVC 
Umbilical venous catheter 

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INVESTIGATOR AGREEMENT PAGE:  
The Sustained Aeration of Infant Lungs (SAIL) Study (Version 2.7_20170315) 
INVESTIGATOR (S) 
• I agree to conduct this clinical study in accordance with the design and specific provisions of 
this protocol and will only make changes in the protocol after notifying the sponsor except 
when necessary to protect the safety, rights, or welfare of subjects. 
 
• I will ensure that the requirements relating to obtaining informed consent and institutional 
review board (IRB) review and approval in 45 CFR 46 are met. 
 
• I will ensure that the requirements relating to obtaining HIPAA authorization following the 
federal mandate for disclosure of access to data and associated privacy protection will be met. 
 
• I agree to report to the sponsor adverse experiences that occur in the course of the 
investigation, and to provide annual reports and a final report in accordance with 45 CFR 46. 
 
• I agree to maintain adequate and accurate records and to make those records available for 
inspection in accordance with 45 CFR 46. 
 
• I will ensure that an IRB that complies with the requirements of 45 CFR 46 will be responsible 
for the initial and continuing review and approval of the clinical investigation.  I also agree to 
promptly report to the IRB all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others.  Additionally, I will not make any changes in the 
research without IRB approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.  
 
• I agree to personally conduct or supervise this investigation and to ensure that all associates, 
colleagues, and employees assisting in the conduct of this study are informed about their 
obligations in meeting these commitments by providing them with copies of the protocol, any 
subsequent protocol amendments, and access to all information furnished by the sponsor. 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
 
Name (Please Print) 
 
Institution 
Once signed, this original shall be maintained in the Regulatory Binder at the clinical center, with a 
copy emailed or faxed to the DCC Project Manager (215-573-6262). 

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Contents 
1. 
Introduction .............................................................................................................................. 9 
1.1. 
Background ........................................................................................................................ 9 
2. 
Study Objectives ...................................................................................................................... 12 
2.1. 
Hypotheses ...................................................................................................................... 12 
2.2. 
Specific Aims .................................................................................................................... 12 
3. 
Study Team ............................................................................................................................. 13 
3.1. 
Research Leadership........................................................................................................ 13 
3.2. 
Participating Clinical Sites................................................................................................ 15 
3.3. 
Data Coordinating Center (DCC)...................................................................................... 15 
3.4. 
NICHD Sponsorship.......................................................................................................... 16 
4. 
Trial Conduct ........................................................................................................................... 16 
4.1. 
Identifying Potential Participants .................................................................................... 16 
4.2. 
Consent ............................................................................................................................ 16 
4.3. 
Study Design .................................................................................................................... 16 
4.4. 
Study Population ............................................................................................................. 16 
4.4.1. 
Inclusion Criteria .............................................................................................................. 16 
4.4.2. 
Exclusion Criteria ............................................................................................................. 17 
4.4.3. 
Trial Withdrawals ............................................................................................................ 17 
4.4.4. 
Randomization Criteria and Methods ............................................................................. 17 
4.5. 
Intervention Maneuvers in Delivery Room ..................................................................... 18 
4.5.1. 
Control Arm Infants ......................................................................................................... 21 
4.5.2. 
Intervention Arm Infants ................................................................................................. 21 
4.5.3. 
Data Collection for Non-eligible Infants .......................................................................... 24 
4.5.4. 
Training and Standardization of Research Intervention ................................................. 24 
4.6. 
Random Allocation in the Delivery Room ....................................................................... 25 
5. 
Study Data ............................................................................................................................... 26 
5.1. 
Maintaining Adherence to Algorithms and Minimizing Protocol Deviations ................. 29 
5.1.1. 
Potential Confounders and Strategy to Limit Impact...................................................... 30 
6. 
Statistical Analysis ................................................................................................................... 31 
6.1. 
Statistical Plan ................................................................................................................. 31 
6.1.1. 
Sample Size Determination ............................................................................................. 31 
6.1.2. 
Methods of Analysis ........................................................................................................ 31 
6.1.3. 
Analysis of Secondary Outcomes .................................................................................... 33 

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6.2. 
Interim Analysis ............................................................................................................... 33 
7. 
Trial Management ................................................................................................................... 35 
7.1. 
Data Security ................................................................................................................... 35 
7.2. 
Data Sharing .................................................................................................................... 35 
7.3. 
Data Safety Monitoring Committee (DSMC) ................................................................... 36 
7.3.1. 
Composition and Function of the DSMC ......................................................................... 36 
8. 
Research Ethics ........................................................................................................................ 38 
8.1. 
Consent Options .............................................................................................................. 38 
8.1.1. 
Consent Approach and Consent Form for Families......................................................... 39 
8.2. 
Risks of Study Participation ............................................................................................. 41 
8.3. 
Data Confidentiality ......................................................................................................... 42 
9. 
Regulatory Oversight ............................................................................................................... 43 
9.1. 
Conflict of Interest ........................................................................................................... 45 
9.2. 
Collecting and Reporting Adverse Events ....................................................................... 45 
9.2.1. 
Adverse Events (AE) ......................................................................................................... 45 
9.2.2. 
Serious Adverse Events (SAE) .......................................................................................... 45 
9.2.3. 
Clinical Events Defined .................................................................................................... 47 
9.2.4. 
Unanticipated Problems .................................................................................................. 47 
9.2.5. 
Adverse Event Management and Reporting ................................................................... 47 
10. Synopsis .................................................................................................................................. 48 
11. References .............................................................................................................................. 49 
 

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1. 
Introduction 
This research study funded by the NICHD, is a Phase III randomized controlled trial (RCT), which aims to 
provide evidence for changing policy or standard of care. The context of this trial is an unacceptable rate 
of poor long-term outcomes of preterm infants born as Extremely Low Gestational Age Newborns 
(ELGAN) <1000 g birthweight (BW), but especially for those born between 23-26 weeks’ gestational age 
(GA). Such infants are the most vulnerable and immature in all organ systems, including the lungs and 
the brain. These infants are at high risk of death and bronchopulmonary dysplasia (BPD) during their 
initial hospitalization, neurodevelopmental impairment (NDI) and pulmonary problems in infancy and 
childhood.  
The SAIL trial focuses on facilitating the difficult transition of these most vulnerable infants from a liquid 
filled in-utero lung to an ex-utero air-filled lung. Sustained Inflation (SI) is a promising delivery room (DR) 
intervention, with evidence of short-term efficacy with minimal risk of additional harm beyond current 
standard accepted Newborn Resuscitation Programme (NRP) Guidelines. This protocol proposes a fully 
informed consenting procedure. We propose to evaluate the impact of a SI in the DR on the need for 
mechanical ventilation in the first week of life which would also impact mortality rates and the incidence 
and severity of BPD. 
1.1. Background 
Extreme prematurity makes the transition from intra-uterine life to extra-uterine life more difficult. 
During this transition - termed the ‘Golden Hour’ – the newborn must generate the critical opening 
pressure to aerate her/his lungs, remove the amniotic fluid and lung liquid to fill the lung with air to 
enable extra-uterine life. This requires an enormous physiological change and energy cost. Normally, 
high ambient oxygen, cord clamping, cold and other external stimuli will trigger breathing. However, the 
ELGAN infant has a compliant chest wall prone to collapse and weak respiratory muscles, and cannot 
cope with the high work of breathing. This work is increased in the presence of retained amniotic  liquid. 
Most ELGANs are born by cesarean delivery, often without adequate labor. This retards the activation of  
the sodium channels (ENaCs), that switch the lung from a Na secreting to a sodium absorbing state, 
ensuring residual lung water.  
We know that establishing uniform aeration also called an ‘open lung’ prevents lung injury.(1)  
Performing this well in the DR provides the best start to the critical first days of life. Yet the best manner 
to achieve this is poorly studied. In this trial we compare two alternative methods that have both 
received an AAP ILCOR-2010 endorsement. Positive-end expiratory pressure (PEEP) is now routinely 
used in the DR to establish and maintain functional residual capacity (FRC) and its use is well supported 
by data. There is some weak evidence that an alternative method, SI may help. Indeed in many parts of 
Europe the practice of SI has become a standard approach (Appendix 1) – Letters from Ulm Germany 
and Leiden Netherlands). However, a lack of high quality evidence and uncertainty about its safety make 
the current creep into more general practice, problematic. 

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The underlying trial rationale is that augmenting PEEP by a SI will facilitate clearance of lung fluid and 
more effectively develop a stable FRC. The SAIL trial will promote evidence-based practice, by 
conducting a 600 patient prospective multi-center trial targeting clinically important outcomes. SAIL will 
randomize eligible infants to one of two methods of ensuring early DR lung aeration:  the initial delivery 
of PEEP alone; or PEEP supplemented by SI. The combined primary outcome,  BPD or death at 36 weeks, 
is well established, robust and clinically meaningful. Treatment assignment will be masked at the time of 
developmental follow-up and the outcome of BPD will be acording to a blinded assessment of the 
Oxygen Reduction Test (ORT).1  The SAIL trial addresses two unanswered, but important questions:  
Firstly, “In preterms 23-26 weeks (GA) who require resuscitation and/or respiratory support in the DR, 
which of two alternative strategies to achieve lung aeration results in the lowest rate of death or BPD at 
36 corrected weeks of age?”  
Secondly, “In preterms 23-26 weeks (GA) who require resuscitation and/or respiratory support in the 
DR, what are the safety profiles of 2 currently used methods in the DR to achieve lung aeration?”  
In addition to this primary outcome, we will describe several clinically relevant and/or physiologically 
relevant secondary outcomes, including: FiO2, respiratory support, surfactant use, radiographic evidence 
of RDS, % of infants ever intubated, head ultrasound, duration of respiratory support; respiratory 
severity score (FIO2 x mean airway pressure).  
There are two defined ancilliary studies that will be conducted within the trial. At one site (Ulm) we will 
have niroscopy brain recordings, and at several sites, we will obtain flow volume pressure records during 
and after SI in the DR.  
 Thousands of babies per year die or develop BPD in the US. BPD is a costly chronic childhood 
illness. In a study of health care expenditure among children, BPD ranked second for total 
payments of $2.4 billion annually (Appendix 2 - http://www.lung.org/lung-
disease/bronchopulmonary-dysplasia/). Survivors with BPD often suffer serious pulmonary 
and/or neurodevelopmental sequelae. While extremely-low birth-weight (<1000 g at birth) 
infants are at high risk of death or BPD, the most vulnerable are those born between 23 and 26 
weeks’ GA. In this population, the rate of death or BPD was 68% in the recent SUPPORT trial.2  
Despite a significant amount of research designed to prevent BPD, there has been little 
improvement in the incidence or severity of the disease. Novel interventions are urgently 
needed.  
The SUPPORT Trial evaluated both continuous positive airway pressure (CPAP) for infants breathing 
spontaneously, and PEEP during intermittent positive pressure ventilation in the DR. Both approaches 
help to establish and maintain FRC, which aerates the newborn lung. Several trials demonstrate that 
CPAP can be safely delivered in the DR, but do not reduce the incidence or severity of BPD.  
These have been taken into account in the design of this trial. At the time of submission of the trial for 
peer-reviewed funding, the ILCOR-AAP 2010 statement (Appendix 3) stated:  

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“End-Expiratory Pressure: “There is no evidence to support or refute the use of CPAP in the delivery 
room in the term baby with respiratory distress.” (Page 1404 column 3). ILCOR states earlier in this 
section, that in preterm babies the situation is different:  
“Although positive end–expiratory pressure (PEEP) has been shown to be beneficial and its use is routine 
during mechanical ventilation of neonates in intensive care units, there have been no studies specifically 
examining PEEP versus no PEEP when PPV is used during establishment of an FRC following birth. 
Nevertheless, PEEP is likely to be beneficial and should be used if suitable equipment is available (Class 
IIb, LOE C). PEEP can easily be given with a flow-inflating bag or T-piece resuscitator, mechanical 
ventilation (Class IIb, LOE B). The most appropriate choice may be guided by local expertise and 
preferences” (Page 1404 Column 2-3). 
• After the meta-analysis contained in (Appendix 4)  of pooled results of the three main trials 
evaluating CPAP vs other approaches for such small infants in the DR – it was clear the point 
estimate favors CPAP. 
• As a result of these considerations, the standard of care at HUP (Appendix 5) has incorporated 
CPAP as the first line in the DR for these very small infants.  In synopsis, this adopted the view 
that: “even for infants who eventually require intubation, there is no evidence of harm 
associated with starting CPAP in the delivery room.   
The approach of using PEEP-CPAP in the DR as an initial means of support has now been widely adopted 
in the US.3  It is now considered as the appropriate standard of care in the Hospital of Pennsylvania 
(HUP) NICU, and a recent quality improvement project targeted successful DR-CPAP intervention. 
Finally to emphasize that our approach does not depart from current standards of care, three very 
recent statements of the Committee on Fetus Newborn of the American Academy of Pediatrics (AAP) 
point out: 
1. Using CPAP immediately after birth with subsequent selective surfactant administration should be 
considered as an alternative to routine intubation with prophylactic or early surfactant administration in 
preterm infants (Strong Recommendation)(Appendix 6) 
This message is reinforced in another recent statement:  
2. Preterm infants treated with early CPAP alone are not at increased risk of adverse outcomes if treatment 
with surfactant is delayed or not given (Level of Evidence: 1).  
3. Early initiation of CPAP may lead to a reduction in duration of mechanical ventilation and postnatal 
corticosteroid therapy (Level of Evidence: 1).(Appendix 7) 
Therefore the use of CPAP in the DR for these infants should be considered a standard of care in North 
America and other developed parts of the world.  
We propose however, that a new approach to actively recruit lung capacity in the DR would reduce the 
need for mechanical ventilation and further decrease morbidity and mortality in the most vulnerable 
preterms.  While the NRP guidelines are accepted as the standard routine resuscitation of premature 
infants, the NRP does not have a specific algorithm for extremely premature infants. The NRP algorithm 

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for term infants is adapted for the premature infant population. The SAIL study is in a unique position to 
offer a possible algorithm specifically designed for the ELGAN population. The NRP Committee has been 
extremely supportive of this trial and wishes to see such a study performed to help guide its future 
advice. 
2. 
Study Objectives 
2.1. Hypotheses  
(i) Early lung recruitment with SI superimposed upon standard PEEP/CPAP in the DR will reduce the need 
for mechanical ventilation in the first seven days of life, and reduce need for surfactant use; and (ii) A 
policy of DR SI on standard PEEP/CPAP recruitment will confer better outcomes at 36 weeks post-
menstrual age (PMA) than standard PEEP/CPAP.  
We will test these hypotheses in a multi-site randomized trial with the following specific aims:  
2.2. Specific Aims  
1) To determine in 600 infants born at 23-26 weeks GA requiring respiratory support at birth, which 
of two lung opening strategies – either a standard PEEP/CPAP of 5-7 cm H2O in the DR, 
compared to early lung recruitment using SI in the DR, results in a lower rate of the combined 
endpoint of death or BPD (using a standardized oxygen reduction test) at 36 weeks PMA.  
2) To compare the rates of other important secondary outcomes such as:  
a. Detailed outcomes of potential importance in the first 10 days of life: 
i. 
Heart rate in the DR 
ii. 
Detailed status on departure from the DR 
iii. 
Use of inotropes on arrival in NICU 
iv. 
Chest X-ray reports showing pneumothorax or new chest drains in the first 48 hours 
of life;  
v. 
Need for new chest drains after NICU admission 
vi. 
Duration of any chest drain in-situ post-DR 
vii. 
Oxygen profile over first 24 hours post DR using hourly FiO2 records 
viii. 
Oxygen profile with highest FiO2 up to 48 hours 
ix. 
Head US and/or MRI findings of intraventricular hemorrhage by all grades but 
especially focusing on grades 3 and 4 by 48 hour and by day 10, if clinically available 
x. 
CXR appearance between days 7-10, if clinically obtained 
b. Components of the primary outcome (i.e. death by 36 weeks PMA or BPD at 
36 weeks PMA  
c. Need for intubation in DR or by 24 hours of age  
 
 
d. Pressure-volume characteristics in the DR (at several but not all sites) 
e. Death or need for positive pressure ventilation at 7 days  
f. Highest FiO2 and Area under the curve FiO2  for first week of life  

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g. Survival to discharge home without BPD, retinopathy of prematurity (grades 3 & 4), or 
significant brain abnormalities on head ultrasound 
h. Pneumothorax and pulmonary interstitial emphysema (PIE) 
i. Duration of respiratory support (ventilation, CPAP, supplemental oxygen)  
j. Retinopathy of prematurity (ROP) stage 3 or greater requiring treatment   
k. Death before discharge  
l. Use of postnatal steroids for treatment of BPD  
m. Length of hospital stay  
n. Neurodevelopmental and respiratory outcome at 22-26 months corrected GA  
3. 
Study Team 
3.1. Research Leadership 
This research group is an experienced, productive team led by five clinical Co-PIs (HK, MK, PD, AtP, HH) 
and one biostatistical Co-PI (SR), who are all experienced clinical trialists, and methodologists or 
biostatisticians. All six have participated in or led multi-center or multi-national studies.  
The Co-PIs will form an Executive Committee that will meet by telephone conference monthly and face-
to-face as need dictates, but at a minimum bi-annually at international meetings. We have shown this is 
feasible in the design of this study and through a combination of telephone discussions and very 
frequent and detailed emails, have established an open, concrete discussion. The Multiple PD/PI 
Leadership Plan details how we will address any potential problems.  
The NICHD Scientist participates in discussions with the investigators during phases of protocol 
development and analyses of results; oversees the overall progress of the study, the pace of subject 
recruitment, and reviews DSMC reports to take appropriate actions.  
 
 

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SAIL STUDY RESEARCH NETWORK 
 

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3.2. Participating Clinical Sites 
The following investigators from diverse United States and international clinical centers will participate 
in the trial. 
Investigator 
Clinical Center 
Location 
Elizabeth Foglia, MD, MSE. 
Hospital of the University of Pennsylvania  
Philadelphia, PA 
Soraya Abbasi, MD 
Pennsylvania Hospital 
Philadelphia, PA 
Martin Keszler, MD 
Women & Infants Hospital of Rhode Island 
Providence, RI 
Francis Poulain, MD 
University of California, Davis   
Davis, CA 
Anup C. Katheria, MD 
Sharp Mary Birch Hospital for Women & Newborns San Diego, CA 
Steve M. Donn, MD 
University of Michigan 
Ann Arbor, MI 
Ursula Guillen, MD, MSE. 
Christiana Care Health System 
Newark, DE 
Claudia T. Cadet, MD 
WakeMed Health 
Raleigh, NC 
Andrew Hopper, MD 
Loma Linda University 
Loma Linda, CA 
Peter Davis, MD, FRAXP 
Royal Women’s Hospital 
Melbourne, Australia 
Arjan te_Pas, MD 
Leiden University Medical Center 
Leiden, Netherlands 
Helmut Hummler, MD 
Children’s Hospital, University of Ulm 
Ulm, Germany 
GianLuca Lista, MD 
Ospedale dei Bambini 
Milan, Italy 
Georg Schmoelzer, MD, PhD Royal Alexandra Hospital 
Edmonton, Canada 
Anton H.L.C. van Kaam, MD, 
PhD 
Emma Children’s Hospital,  
AMC University of Amsterdam 
Amsterdam, 
Netherlands 
Burkhard Simma, MD 
Landeskrankenhaus, Feldkirch, Austria 
Feldkirch, Austria 
Daniel Klotz, MD 
Universitätsklinikum Freiburg 
Freiburg, Germany 
Juin Yee Kong, MD 
KK Women’s and Children’s Hospital 
Singapore 
Helen Liley, MB, ChB, FRACP Mater Mother’s Hospital 
Brisbane, Australia 
Han-Suk Kim, MD. PhD 
Seoul National University Children’s Hospital 
Seoul, South Korea 
Won Soon Park,MD, PhD 
Samsung Medical Center 
Seoul, South Korea 
 
3.3. Data Coordinating Center (DCC) 
Data from all clinical participating sites will be centrally managed by the Data Coordinating Center (DCC) 
housed at the University of Pennsylvania, Philadelphia, PA. The DCC will be directed by Dr. Ratcliffe. The 
DCC is comprised of four parts: Biostatistics, Project Management, Data Management and Information 
Systems. The DCC will provide statistical collaboration, data management and information technology 
support for the development and conduct of the trial. The DCC is responsible for regulatory oversight 
and coordination of protocol modifications at the participating clinical sites. DCC Personnel are shown in 
the table below.  

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DCC Team  
Expertise 
Role 
Sarah Ratcliffe 
Biostatistics 
Co-PI / DCC director / Faculty Biostatistician 
Russ Localio 
Biostatistics 
Co-I / Faculty Biostatistician 
Sherry Han 
Biostatistics 
Sr. Statistician (BAC) 
Min Du 
Biostatistics 
Programmer (BAC) 
Clinical Research 
Computing Unit 
Research Operations 
Service Center 
Project Management, Data Management, Research 
Technology 
3.4. NICHD Sponsorship  
The NICHD has funded this study based on its scientific importance, the opinion by the study section, 
and the approval from the NICHD National Advisory Council. 
4. 
Trial Conduct  
4.1. Identifying Potential Participants 
Research coordinators will evaluate maternal admissions to the Labor and Delivery Unit at the clinical 
site to preliminarily assess eligibility based on estimated gestational age and maternal labor status.  
4.2. Consent 
A waiver or deferred consent approach was initially proposed but with IRB recommendations, a full 
antenatal consent procedure has been adopted. These are fully described in Section 8, ‘Research Ethics’.  
4.3. Study Design  
This prospective multi-site, multi-national randomized intention-to-treat, trial will randomize 600 infants 
into one of two arms:  
Group 1: Standard of care – DR PEEP/CPAP 5-7 cm H2O, or PPV and NRP compliant practice in the 
DR. 
Group 2: DR SI and standard PEEP-CPAP of 5-7 cm H2O, and NRP compliant practice in the DR. 
Although un-blinded intervention is necessary, bias is controlled by blinded outcome assessment of BPD 
at 36 weeks, neurodevelopment and an objective outcome of death. This blinded 36 week PMA 
assessment will be performed by clinicians (nurses, RTs, physicians) who did not look after that infant.  
Parents will not be blinded to the intervention and will be informed of the allocation after the infant has 
been admitted to the neonatal intensive unit.   
4.4. Study Population 
4.4.1. Inclusion Criteria 
Infants who are born in participating NICUs (which do not use prophylactic surfactant) and who fulfill 
the following inclusion criteria are eligible for enrollment: (a) Gestational age (GA) at least 23 weeks 
but less than 27 completed weeks by best obstetrical estimate; (b) requiring 
resuscitation/respiratory intervention at birth – “apneic, labored breathing, gasping” (as defined in 
NRP 2011 AAP 6th Edition p. 45.)4 

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The window for determining eligibility is up to 30 seconds. The decision making process in 
determining if an infant is eligible is to be done simultaneously while performing the initial steps, 
such as: 
1) Placing the infant on the resuscitation trolley;  
2) Suction airway, open airway and proceed with CPAP;  
3) Wrap the infant in saran wrap/neo wrap for temperature stability;  
4) Assessment of heart rate and respiratory effort ; and  
5) Placement of the pulse oximeter probe.  
All 5 initial steps take place at the same time by various members of the DR team.  This is consistent 
with the NRP guidelines which allows up to 30 seconds to accomplish the initial steps and determine 
the need for PPV. This has been independently verified in several sites (Leiden; Ulm; Edmonton; and 
Hospital University Pennyslvania in repeated simulations). 
4.4.2. Exclusion Criteria 
a. Considered non-viable by the attending neonatologist  
b. Refusal of antenatal informed consent   
c. Known major anomalies, pulmonary hypoplasia  
d. Mothers who are unable to consent for their medical care and who do not have a surrogate 
guardian will not be approached for consent.  
4.4.3. Trial Withdrawals 
It is anticipated that there will be a small number of infants who, because of acute clinical 
deterioration are treated according to the preference of their medical team rather than by study 
protocol. However, their outcomes will be measured and analyzed according to original allocation by 
intention-to-treat principles. 
4.4.4. Randomization Criteria and Methods  
Consent:  
As the lead site, the Hospital of University of Pennsylvania (HUP) will provide the template for a 
study wide consent approach.  This template  asks that each site approach the IRB with request for 
antenatal consent. We recognize that at some sites an approach will be made (or have already has 
been made) in requesting their respective IRBs for deferred or waiver of consent for their particular 
institiution.    
This protocol  assumes the approach for antenatal consent as per the recommendations of the 
University of Pennsylvania’s IRB.  In those sites where antenatal consent is being sought, parents of 
potentially eligible infants from  23 +0 to 26 + 6 GA who may conform to the inclusion and exclusion 
criteria will be approached by the clinical study team (either a research coordinator or the site 
investigator) in the antenatal period in order to offer study participation.  

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Randomization: 
A randomization schema will be developed centrally by the DCC at the University of Pennsylvania, 
and implemented at each clinical site using color-coded opaque sealed envelopes to ensure 
allocation concealment and proper and efficient randomization. Envelopes will be packaged and 
shipped to each study site.  
A permuted block randomization procedure will be used to formulate assignment lists in order to 
assure close to equal numbers of subjects in each treatment group. Randomly permutated blocks 
with unequal blocks of varying sizes, and allocation ratio within each block of 1, will be used. The 
block sizes will be determined by site in order to ensure balance between treatment arms in sites 
with potentially small, or large, subject enrollment. 
We have chosen to stratify the randomization scheme by clinical site, and gestational age (two strata 
23 & 24 weeks versus 25 & 26 weeks). Stratifying on any more variables (such as gender) is not 
feasible with the potentially small enrollment numbers expected at some sites. We will perform a 
planned adjustment following the end of the trial to adjust for gender. Use of separate 
randomization schedules by site (ie stratified by centre, with each site having the same allocation 
ratio of treatment groups) ensures comparability of the treatment groups with regard to the patient 
mix coming from the various sites in the trial. This assurance is important because the populations 
can differ widely with regard to subject characteristics. Further, there may be subtle differences in 
the standard of care from site to site, despite the fact that this study has a well-defined plan and 
strict inclusion and exclusion criteria. Finally, stratification by gestational age is needed, as it is well 
know that mortality outcomes improve as the gestational age increases. 
While there are clearly subject-specific variables that will be observed and recorded before 
randomization that could be used for stratification, such as gender, there are a number of problems 
with including more stratification variables. Of most concern, stratification by multiple variables 
would likely result in small numbers per group and a fairly large chance of departure from the 
desired allocation ratio. Since we are proposing a study with 300 subjects per group, the groups 
should be large enough that stratification should not be necessary to assure that the two arms will 
have approximately equal representation of the major confounding variables. However, a careful 
post-hoc analysis will be carried out to assure that the allocation was, in fact, equal. Analysis 
procedures involving post-stratification, and multiple regression will be used to adjust for any 
baseline group differences. 
4.5. Intervention Maneuvers in Delivery Room 
Because this is an international multi-site trial, we are aware that International sites may have minor 
modifications of the below, all of which will be assessed for trial approval by the Steering Committee. 
However we do make reference below to “site clinical local practices”. If such minor variations in these 
will not affect the validity and integrity of the tral, they will be allowed.  
At all sites where antenatal consent has been obtained, or in some sites where the local IRB has granted 
waiver, eligible infants (230-266 completed weeks GA) will be taken to a resuscitation trolley, placed in a 

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plastic wrap and have a SpO2 probe attached to the right hand (NRP p.54).4 The infant’s airway will be 
cleared and the infant will be commenced on mask or nasal prong CPAP at 5-7 cm H2O and FiO2 0.3 via a 
T-piece. 
A wide range of authorities have now accepted this in the peer-reviewed press as a standard procedure 
in 2013-2014.  We have ensured that we are fully compliant with ILCOR 2010 and NRP 2011 standards, 
using CPAP or PEEP. We have discussed aspects of this in the study background section, and referenced 
the January published latest statements from the Fetus and Newborn Committee of the AAP.5, 6  
(Appendix 7) Our NRP compliant approach  is attested to in several other ways, including the approval of 
the DSMB that includes Dr. Kattwinkel (one of the co-founders of the AAP NRP program); the inclusion in 
our group of a NRP committee member (Dr. Ades from CHOP-HUP);  and consistency with the Quality 
Program initiatives of the DR processes in HUP. (Appendix 8).For the trial, the time of birth has been set 
as final emergence of the infant from delivery. The time of cord clamping will be recorded. Finally, the 
time for the Study Intervention (see Figure 1 below) is measured from the point of the infant being 
placed on the resuscitation trolley (defined as time zero).  
Thereafter, an infant with inadequate respiration defined as gasping or apneic; or is bradycardic defined 
as  HR<100 bpm and not rising (as labelled in the algorithm diagram: Figure 1) will be eligible for the SAIL 
trial.  Time in which to determine eligibility is 30 seconds, however an infant can declare himself/herself 
in less time.  The initial 30 seconds are congruent with NRP guidelines.  
Infants who are not eligible for the SAIL trial will be continued on CPAP, and all further resuscitative 
measures will be made according to local clinical protocols. 
For infants who are eligible for the SAIL trial, the randomization envelope will be opened, and the 
treatment allocation will be announced to the clinical team.  Thereafter, the protocol algorithm will be 
followed for babies who are randomized to the SI intervention.  Infants who are randomized to the 
control arm will be treated according to local clinical protocols. (See 4.5.1 for more detail on the control 
arm infants). 
Regarding choice of pressures: “The primary measure of adequate initial ventilation is prompt 
improvement in heart rate. Chest wall movement should be assessed if heart rate does not improve. The 
initial peak inflating pressures needed are variable and unpredictable and should be individualized to 
achieve an increase in heart rate or movement of the chest with each breath. Inflation pressure should 
be monitored; an initial inflation pressure of 20 cm H2O may be effective, but 30 to 40 cm H2O may be 
required in some term babies without spontaneous ventilation if circumstances preclude the use of 
pressure monitoring, the minimal inflation required to achieve an increase  in heart rate should be 
used.”   The choice of pressure is discussed further below under section 4.5.2.  
 
 

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Figure 1: The overall schema for eligible versus non-eligible infants 
Infant  23-26 weeks
Randomize
Place in bag, clear secretions, attach pulse oximeter right arm
CPAP
Control – IPPV (20-25 cm H2O);
Treat as standard for NRP
Sustained Inflation 20 
cm PIP x 15 s 
Active, crying, HR>100
IPPV:  Inactive, not crying, or 
HR<100 
Not 
eligible
SI 25 PIP x 15 s 
Crying, Active,    HR
Not crying, HR<100
Active, crying, HR>100
nCPAP
15-30sec
Ongoing 
requirement 
for IPPV
IPPV*
nCPAP
Requires ongoing IPPV
IPPV*
5 minutes
* = endotracheal intubation may be considered
 
 
 

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4.5.1. Control Arm Infants 
Infants randomized to this arm will follow standard NRP guidelines.  While starting on CPAP, this may 
include the provision of T-piece resuscitator (positive pressure) ventilation with peak pressures set 
initially at 20 cm H2O for 15 seconds, and if needed subsequently, increased to peak pressure of 25 
H20 cm, or as local clinical practices allow. Corrections by MR. SOPA are to be applied as 
recommended by NRP guidelines. These are discussed in fuller detail below under 4.5.2. 
4.5.2. Intervention Arm Infants 
All respiratory support is to be administered via the T-piece resuscitator and either face mask, 
nasopharyngeal tube (NPT) or a shortened endotracheal tube placed as an NPT. The Mountain trial 
has reported that there is no difference in interface. (Appendix 9) SI will be delivered via T-piece 
resuscitator, as this device has been shown to be the only one capable of effective delivery of CPAP 
and SI (Hussey SG 2004, Klingerberg C 2011).  
The choice of initial pressure for the SI is based on pathophysiology, literature, local practice or other 
and available data. While animal studies suggest that inflation pressures as high as 35 cm H2O are 
needed in animals with no spontaneous effort and no antenatal steroids7-11, human trials suggest 
that when the lungs are partially aerated as a result of the infant’s respiratory effort, pressures as 
low as 20 cm H2O may be sufficient. A single SI with a pressure of 25 cm H2O was used in a recent 
cohort study12 without apparent adverse effects. Escalating SI pressure ranging from 20 to 30 cm 
H2O for up to 3 SIs was used by the other two studies. The first reported that 67% of infants required 
25 cm and 8% received SI of 30 cm H2O.13 SIs of 20 cm H2O were adequate in 60% of infant in the 
other trial, while 40% of infants required 25 cm H2O and of those, the majority had an inadequate 
response and required intubation14. At that center, SI of up to 30 cm H2O is now used as part of 
standard DR care.  
Thus, eligible infants will be given the first SI using pressure of 20 cm H2O.   An assessment for 
respiratory effort and heart rate will be made.  Infants with adequate respiratory effort and heart 
rate above 100 bpm will continue on CPAP as study intervention has ended for these infants and 
they revert to standard NRP procedures.  
For those infants following the first SI who remain without adequate respiratory effort, a second SI 
using a pressure of 25 cm H20 for 15 seconds will be delivered.   In the interval between the first SI 
and the second SI, the team will follow standard  NRP procedures as described in the next paragraph 
(MR SOPA). Decisions about adequacy of the SI will be based on infant’s response as judged by 
improving HR, respiratory effort and SPO2.  
During this period between Sis, as per NRP recommendations, adjustments can be made to ensure 
no residual lack of seal or obstruction is impeding the infant, resuscitation will proceed according to 
the first  four steps of the “MR. SOPA rule”. (i.e. Mask Readjustment; Suction airway; Open mouth.) 
In both the NRP algorithm as well as the SI algorithm, MR. SOPA is incorporated in the step outlined 
as “take corrective ventilation steps”. Last, if the infant is eligible for a second SI, the clinician will 

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ensure airway patency and deliver the second SI with a pressure 5 cm higher than the initial 
pressure. This step is in accordance with the P step of MR. SOPA. 
The final ‘A’ in MR. SOPA stands for Airway. There will be rare situations where the clinician must 
respond with intubation immediately – such infants will be also randomized into an SI or standard 
arm. While these infants data will be pooled, it will also be treated separately in a sub-group 
analysis.  At any point in the algorithm, if the  HR is < 60 and not increasing, PPV may be given with 
rate in accordance with NRP and peak inspiratory pressure  equal to the SI that would otherwise be 
performed.  Observation after a  15 second period will assess whether there is an improving heart 
rate. If the heart rate improves to >60, the algorithm will be resumed from the point of departure. 
Throughout the entire period, cardiac compressions will start if HR remains < 60 despite effective 
respiratory support for > 30 seconds.  
Finally, Figure 1 shows two red lines. The first is the initial assessment point which by 30 seconds 
must be completed as according to NRP. However the second dotted redline indicates that by 5 
minutes there may have been a progression towards intubation. This decision point may be reached 
by 2 minutes or even before.  
The modified but NRP compatible procedures are shown for the SI arm in more detail in Figure 2. 
 
 

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Figure 2: Algorithm For infants In Intervention arm directly compared to the NRP algorithm. 
 
The potential risks of this maneuver are described in Section 8 and in the adverse event reporting 
section. The main risk anticipated is the potential for a pneumothorax. However, we do note that not 
only has an excess risk not been seen in the available randomized data to date, but the pressures 
stipulated in the algorithm are within the ranges of those recommended by NRP for conventional 
resuscitation. The DCC will monitor carefully for potential excess risk, and some of the secondary 
objectives are also part of the materials in adverse event reporting and will be transmitted at 
appropriate intervals to the DSMC. 

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4.5.3. Data Collection for Non-eligible Infants 
To complete the patient flow description, this protocol addresses infants in the inclusion GA who are 
not eligible to be randomized. By definition this includes infants whose parent has refused to 
consent. We seek approval to capture limited data for this group of infants. There are two reasons 
for collecting this valuable information:  
• The dearth of information about DR practices in this birthweight range of infants 
• The known high potential for selection bias following the use of antenatal consent 
procedures.17, 18    
Data Collection for these infants will not include any HIPPA protected priviliged information. We will 
be collecting the following information from parents who refused consent: 
Data Collection Topic 
Specific Data Elements 
Delivery Room Data 
Month/Year of birth; time of cord clamping (recorded as mm:ss after 
birth); birth weight; Apgar score at 1 and 5 min; gender; NRP guidelines 
used in the resuscitation of the infant such as respiratory status; 
procedures if any (intubation, chest compression, administration of 
epinephrine; surfactant delivery; UAC/UVC placement; chest tube 
placement; final respiratory status before leaving DR; and outcome of 
resuscitation. 
Maternal Data Form 
gravid para status, exposure to antenatal steroids and type; maternal 
ethnicity/race;  antenatal corticosteroids (if yes, number of courses); 
any medications given to prolong pregnancy including tocolytics; 
diagnosis of diabetes during pregnancy (insulin dependent); placental 
abruption; chorioamnionitis; membranes rupture > 24 hours before 
delivery; mode of delivery 
 
4.5.4. Training and Standardization of Research Intervention 
A training video has been produced for use in training the staff at all participating clinical sites. (It will 
also be translated into Italian; neither the Dutch nor German sites will need translation). The video 
will be used to train the research team about the protocol but also can be viewed when the team 
has been alerted that a potentially eligible SAIL baby may be born shortly. This video can be accessed 
from the SAIL Trial Website which will be created and maintained by the DCC. Should any university 
site deem this an unsafe site, the video will be sent as a file to the respective hospital site 
coordinator to load on appropriate computers.Should any university site deem this an unsafe site, 
the video will be sent as a file to the respective hospital site coordinator to load on appropriate 
computers 

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To assess fidelity of the research intervention across sites, a variety of methods will be used.  
• A main feature of our methods here hinge on the use of video recordings. Video capability 
during resuscitation for quality control purposes is available at UCSD, Calgary, Ulm, and 
Milan. A random sample of infants at each of these sites will be evaluated by the quality team 
(led by the Philadelphia team of Drs. Ades, Foglia, Posencheg, and Nadkarni).   
• A training checklist will be generated for those who perform SI and will include simulation. 
The PI at each site will be responsible to ensure that each person performing SI has been 
properly trained. 
4.6. Random Allocation in the Delivery Room 
Following informed consent, the mechanics of the randomization maneuver in the DR addresses the 
following aspects:  
• Twins and multiples will be randomized as a unit, using a single envelope.  
• Envelopes will be kept immediately outside the DR, at a safe designated site suitable for 
each site.  
There will be between 3-5 envelopes for each of the gestational age strata in each location. This will 
ensure that in the hurry around a pending delivery there is no excess fumbling. Selection will be 
sequential and the lowest number marked on the envelope will be taken. 
The next numbered envelope will be taken into the DR by the NICU-DR team. Opening of the envelope, 
and thus randomization, will only be performed when the infant has been delivered and deemed to 
require respiratory assistance. Within 15-30 seconds the assessment of whether or not the baby is 
eligible to be randomized is possible to make in a safe manner.  
We have undertaken extensive simulation of this procedure and it does not introduce time-delays. We 
provide here a video clip showing this procedure in action at one of these simulations on the SAIL Trial 
website. Our peocedure is modeled on those undertaken during the pivotal COIN trial where a member 
of our Steering Committee (P.Davis Melbourne) was a co-investigator. In addition Dr Kirpalani was one 
of the site investigators for the COIN trial at McMaster University, Canada, where the process of 
randomization also did not impede safe practices in the DR. 
Thus opening of the envelope will not impede appropriate delivery of care. All opened envelopes and 
assignments will be kept in the logs of the site. The research study coordinator will be available as a 
back-up for the clinical Neonatal DR delivery team. 
 
 

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5. 
Study Data 
The following is a table of details that will be collected, and it is itemized by day of collection. It should 
be noted that only the details of the sustained inflation maneuver itself, and the screening log for 
eligible patients, is unique to this study. All other data points are routinely measured. There are no blood 
tests or data being collected that are not already routine clinical data.  
Data Collection Topic 
Specific Data Elements 
Specific time interval 
Eligibility and 
Randomization Data Form 
Clinical data: meets inclusion criteria and 
none of exclusion criteria; eligibility 
confirmed 
Research: date and time of 
randomization, and allocation of 
treatment arm (control vs intervention) 
First 30 seconds of birth 
Delivery Room (DR) Data 
Form 
RESEARCH DATA collected: time infant is 
placed on resuscitation trolley; time of 
specific maneuver; 1st sustained inflation 
and exact pressure measurement x 15 
seconds; time of 2nd sustained inflation 
and exact pressure measurement x 15 
seconds; and use of ventilator vs T-piece 
Research intervention takes 
place within the first 30 
seconds up to 1 - 2 minutes 
of life 
Clinical data: time of birth, time of cord 
clamping, NRP guidelines used in the 
resuscitation of the infant such as 
respiratory status; blood gas values 
including glucose and 
hemoglobin/hematocrit values; 
procedures if any (intubation, chest 
compression, administration of 
epinephrine; surfactant delivery; 
UAC/UVC placement; chest tube 
placement and additional medications; 
final respiratory status before leaving DR; 
and outcome of resuscitation. 
Additional clinical information: date and 
time of birth, birth weight, Apgar score at 
1 and 5 min, and gender 
Certain clinical time points 
as dictated by the 
resuscitation process in the 
DR; data should be 
completed within first 48 
hours 

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Data Collection Topic 
Specific Data Elements 
Specific time interval 
Respiratory function 
measurements of inflations 
and physiologic monitoring 
(Obtained only at a subset of 
sites) 
Inflation characteristics: pressure, flow, 
tidal volume, exhaled CO2 
Physiologic monitoring: heart rate, 
oxygen saturation, delivered oxygen 
concentration 
First 10 minutes of life 
Delivery Room Video 
recording (obtained only at a 
subset of sites; transferred 
and destroyed after analysis) 
Video recordings of the infant during the 
initial resuscitation and stabilization 
Up to the first 30 minutes of 
life 
Adverse Events 
See Section 9.2 for detailed information. 
Specific events during the 
first 10 days of life; 
thereafter continuing AE 
reporting structures are in 
place until the infant 
reaches 36 weeks GA 
SNAPPE Score 
Clinical data: severity score that is 
compiled by using clinical parameters 
within the first 12 hours of life, such as 
lowest pH, PaO2 and corresponding FiO2 
and MAP, urine output and presence of 
seizures   
Completed by first week of 
life 
Daily Respiratory Status for 
First Week of Life 
Clinical: current respiratory  status at 
noon each day to include if applicable, 
respiratory support (CPAP, noninvasive 
PPV, invasive PPV); specific ventilatory 
settings; surfactant administration 
Infant’s respiratory rate, highest FiO2 
from previous time point and 
corresponding SpO2 
Completed for every day for 
the first week of life 

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Data Collection Topic 
Specific Data Elements 
Specific time interval 
Daily Assessment for First 
Week of Life 
Clinical: birth weight and head 
circumference; antibiotics, antifungals, 
indomethacin or ibuprofen, caffeine or 
other methylxanthines;  furosemide or 
other loop diuretic; thiazide diuretic; 
corticosteroids, inhaled corticosteroids, 
inhaled nitric oxide, inhaled 
bronchodilator; vitamin A IM, 
erythropoietin; red blood cell transfusion, 
any paralytic agent; any anticonvulsants,  
any milk feed or formula, any breast 
feeding and any parental nutrition  
Clinical radiographic data, if available: 
head ultrasound or MRI, number of CXR, 
abdominal films 
Completed for every day for 
the first week of life 
Maternal Data Form 
Clinical: mother’s age, gravid para status, 
exposure to antenatal steroids and type; 
maternal ethnicity; maternal education, 
any medications given to prolong 
pregnancy including tocolytics; placental 
abruption; chorioamnionitis; membranes 
rupture > 24 hours before delivery; mode 
of delivery 
Completed within one week 
of enrollment 
Weekly Respiratory Status 
until 36 wks PMA 
Clinical: current respiratory  status at 
noon once/week to include if applicable, 
respiratory support (CPAP, noninvasive 
PPV, invasive PPV); specific ventilatory 
settings 
Infant’s respiratory rate, highest FiO2 
from previous time point and 
corresponding SpO2 
Collected weekly from 2nd 
week of life until 36 weeks 
PMA 
Weekly Assessment until 36 
wks PMA 
Same as above with the exception of 
weekly head circumference instead of at 
birth and date of successful extubation 
defined as extubation for greater than 48 
hours 
Can be completed once a 
week (does not need to be a 
specific day of the week) 
Respiratory Status at 36 wks 
PMA 
Clinical data: exact 36 wks PMA date; 
respiratory status (RA, NC, CPAP, 
invasive/non-invasive PPV), 
If applicable pass/fail Oxygen Reduction 
Test (ORT) 
Can be completed within 
one week of reaching 36 
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Data Collection Topic 
Specific Data Elements 
Specific time interval 
Discharge Status 
Clinical data: date of discharge or death, 
co-enrolled in other clinical trials, and 
respiratory status 
Once a baby has been 
discharged, reached 44 
weeks PMA or died, 
whichever occurs first 
Record of Death 
Clinical: date of death, primary cause of 
death; autopsy performed, if yes, provide 
narrative 
If applicable 
Neonatal Outcome Data  
Clinical data: PDA (treated Y/N), IVH 
(grade), ROP stage > 1, BPD, and positive 
blood culture sepsis, and other 
complications 
Once a baby has been 
discharged, reached 44 
weeks PMA or died, 
whichever occurs first 
Late Outcome Data 
Clinical data: final date of discharge, 
transfer or death if after 44 weeks PMA; 
reason for continued hospitalization 
beyond 44 weeks PMA 
If applicable, for infants who 
remain in hospital past 44 
weeks PMA 
Transfer Form 
Clinical data: date of transfer, transfer to 
medical facility, foster care, etc. 
If applicable, for infants who 
are transferred to an 
outside facility prior to 
reaching 36 weeks PMA 
Follow-up Assessment at 22-
26 months cGA 
Clinical data: the incidence of ambulatory 
and non-ambulatory CP defined by Gross 
Motor Function Score (GMFCS); 
hydrocephalus shunt, microcephaly, or 
seizure disorder; presence of respiratory 
disease necessitating readmission before 
22-26 months follow-up; all individual 
components of the composite outcome 
of Neurodevelopment Impairment NDI or 
death, including cognitive outcomes at 
follow-up at 1 SD cut-off on the Bayley 
Scale of Infant Development BSID III 
standardized scales, BSID III cognitive, 
language and motor scores at 2 SD cut-
offs (<70) at follow-up.  
Once a baby has had a 22-26 
month cGA follow-up visit in 
clinic 
 
5.1. Maintaining Adherence to Algorithms and Minimizing Protocol Deviations  
Extensive education and training will be undertaken to ensure technical proficiency and compliance with 
the protocol. A ‘boot-camp’ will be run at the start of the study by experienced study members (Peter 
Davis, Arjan tePas, Helmut Hummler, Anne Ades, Vinay Nadkarni, Robert Berg, Aasma Chaudhary). This 
will ‘certify’ the site PIs, who will then be in a position to train their own site-members. This training will 
be developed by the CCC Co-PIs and carried out locally by each site PI. A limited run-in period during 

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which SIs will be implemented in delivery room care will precede study initiation at each center in order 
to establish a level of comfort and overcome the learning curve effect. To further ensure adherence, we 
will complete a training video to be used as a refresher and training material for delivery room staff, 
fellows, and attendings. This will certify a site PI, who will be the gold standard trainer at her/his site. 
Site visits will be performed after 10 infants have been enrolled at each site, to examine site comfort and 
performance of the SI, as well as records kept, and trial functioning. At each site, a single SI per 2 months 
will be videotaped and reviewed at HUP for reproducibility and consistency. In addition, experts in 
simulation – Anne Ades, Elizabeth Foglia and Aasma Chaudhary will develop SI education.  
5.1.1. Potential Confounders and Strategy to Limit Impact 
Severity of initial illness:  Randomization should achieve balance at baseline. Adjustment for SNAPPE 
scores on admission to the NICU will be performed during the analysis of the primary outcome. 
Site Variation:  Randomization will be stratified by site. 
General respiratory management in the DR and beyond:  Local unit protocols will be followed with 
respect to aspects of respiratory support not specifically addressed in the study interventions. In 
general, after initial resuscitation, CPAP will be the initial mode of respiratory support in reasonably 
vigorous infants. Intubation will be reserved for infants who remain apneic, are without adequate 
respiratory effort, or have persistent bradycardia. Surfactant for RDS prophylaxis will not be given in 
the DR prior to SI (if so randomized), even if the infant is intubated. Caffeine will be administered to 
infants if needed for respiratory support.  
Extubation and intubation guidelines:  Continued need for mechanical ventilation is associated with 
BPD. We adopt a uniform guideline to intubation and extubation, though clinical circumstances may 
preclude strict adherence to guidelines at all times. There is no consensus about weaning babies 
from mechanical ventilation. Therefore, the proposed extubation guidelines are based on consensus 
and criteria used in several current and recent large clinical trials. On a daily basis the infant will be 
assessed for ability to wean from ventilation. We will strongly encourage extubation to be attempted 
within 24 hours after meeting all following criteria:  PCO2 < 55 mm Hg and a pH >7.25, FiO2 of < 0.4 
with an SpO2 of > 88% or higher, mean airway pressure of  < 8 cm of water, and hemodynamic 
stability  and without evidence of clinically significant patent ductus arteriosus. All infants will have 
received caffeine prior to an extubation attempt. Extubation may be attempted at higher settings at 
the discretion of the clinical team. Following extubation all infants should be placed on nasal CPAP or 
NIPPV, not on nasal cannula or oxihood. In unplanned extubations, the infant will be given an 
opportunity to remain extubated, if heart rate and oxygen saturations are maintained without 
excessively high FiO2 or work of breathing. Extubation will be considered successful if the infant 
remains extubated for at least 48 hours. Reintubation will be at the discretion of the clinical team 
managing the infant. 
Demographic variables:  The next section describes the analytical plan to examine the key covariates 
of gender, antenatal corticosteroids, multiples, and week of gestation.19 

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All of these instructions and definitions will be written into an Operating Manual to be used as the 
initial source for teaching sites and their staff, and on-going re-education.  
6. 
Statistical Analysis 
The Data Coordinating Center (DCC) will be housed at the University of Pennslyvania and submitting a 
separate IRB approval request to the IRB. The DCC is comprised of four parts: Biostatistics, Project 
Management, Data Management and Research Technology. 
Biostatistical support will provide centralized randomization, publication support, interim analyses and 
statistical analysis plans under the direction of Drs. Ratcliffe and Localio. Project management will 
coordinate activities between the scientific and operations teams and manage sites. Data Management 
will include case report form (CRF) design, management and entry, data quality assurance and reporting. 
Information Systems will include database design and system support. 
6.1. Statistical Plan 
6.1.1. Sample Size Determination 
Sample size is based on a possible reduction in risk of neonatal mortality/BDP in infants at 36 weeks 
PMA receiving the SI intervention compared to those who receive the standard PEEP/CPAP. The 
significance level was set at α=0.038 (due to the interim analyses), and power at 80%. Based on 
information from the recent multi-center NICHD SUPPORT trial2 and the COIN trial,20 we estimate 
that the baseline rate of neonatal mortality/BDP in the standard or care (control) arm by 36 weeks is 
65%.  
In order to detect an absolute risk reduction of 12.5%, 263 subjects per treatment arm are required. 
We anticipate virtually no loss to follow-up for the primary endpoint as infants will likely still be 
hospitalized because of their condition, will be under constant and continuing medical care. We have 
inflated the estimate by 1.12 to allow for twins and multiples to be randomized together. With this 
inflation in mind, the target sample size for this study is 300 subjects per arm. 
For the secondary outcomes available in all subjects, with 263 subjects per arm (ignoring the twin 
correction factor), there will be 80% power to detect a difference of 0.24 standard deviation units in 
continuous outcomes, and a hazard ratio of 0.77 in survival outcomes under a proportional hazards 
assumption.  Some secondary outcomes will not be available due to death of the infant, or loss to 
follow-up after discharge from the NICU. Overestimating these rates at 50%, we assume 130 subjects 
per arm will be available for the longer term secondary outcomes. With this sample size we will still 
have sufficient power to detect a clinically meaningful difference of at least 17% in event rates (or 
odds ratio of at least 2.0). 
6.1.2. Methods of Analysis 
The proposed study is a two-arm parallel design of two alternative courses of treatment. A 
conventional “as-randomized” analysis (or “intention-to-treat” analysis) will estimate whether the 

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experimental therapy is superior to conventional therapy in avoiding treatment failure, and is at 
least as good as conventional therapy in avoiding adverse events. 
SAS will be used for secondary data management and descriptive statistics. SAS datasets will be 
downloaded at least weekly from the study database for analysis. Graphics will be prepared using 
Stata v11 (or later) (Stata Corp, San Antonio TX, 2009) and the R programming package (The R 
Foundation for Statistical Computing, Vienna, Austria, 2011). Analyses will be implemented in SAS. 
6.1.2.1. 
Descriptive Statistics 
Although randomization at baseline should balance observed and unobserved differences between 
the treatment arms by measured and unmeasured confounders, extra precautions are needed to 
guard against the potential bias of baseline covariates with chance imbalance from finite sample 
sizes. Initial analysis will describe the distribution of data. We will characterize both treatment arms 
by demographic variables and all covariates of interest. Means, standard deviations, medians, and 
ranges will be computed for measured continuous variables; marginal distributions will be used for 
categorical factors. Graphical methods including histograms, scatterplots, and boxplots, will be used 
in order to understand aspects of data quality and examine assumptions (such as normality) 
underlying statistical models. 
6.1.2.2. 
Analysis of Primary Outcome 
The primary endpoint to be used for efficacy evaluation is the rate of Death or BPD at 36 weeks 
gestation age. The primary hypothesis to be tested is that the treatment therapy results in a 
decreased event rate. Although a proportion’s test is used for sample size calculations, rates will be 
compared using logistic regression, which will allow for control of covariates, as well as investigation 
of effect modification. Potential covariates include gender, gestational age, initial heart rate, 
maternal corticosteriods use, and small for gestational age (SGA). Clinical site will be used as a 
stratifying factor to control for any confounding by site through residual, site-level treatment 
imbalance. The logistic regression will be estimated using a generalized estimating equation (GEE) in 
order to adjust for the inherent correlation expected with multiples. Standard regression diagnostics 
will be used to assess model adequacy, and to examine for potential outlying or influential data 
points.  
Prior studies offer no basis for assuming a priori interactions between treatment arms and 
subgroups defined by sex, race/ethnicity, gestational age, site or a combination of these groups, 
beyond that already controlled for in the randomization. For that reason, preplanned tests for 
interactions with treatment assignment are not warranted, and not powered for. We propose, 
however, to table all results by subgroups for descriptive purposes and to explore in secondary 
analyses possible subgroup differences by treatment group, solely for purposes of generating 
hypotheses for future studies. In particular, there is interest in exploring subgroups defined by:  
• Consenting procedure which may vary by site (antenatal vs. deferred consent). While consenting 
procedure differences may result in some selection bias, this will be implicity adjusted for with 

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the already planned clinical site stratification factor. Additionally, the sample size still results in 
80% power at α=0.038 for the primary outcome even if the selection bias results in a reduced 
control arm rate. 
• Route of treatment (facemask vs. nasopharyngeal tube). While not expected to modify the 
intervention effectiveness, exploring this difference will be important for future study design and 
clinical practice. 
• Enrollment date. Clinical practices unrelated to this intervention, as well as increased 
intervention experience, could result in changes in the clinical effectiveness of the intervention 
over time (positively or negatively). We will explore graphically any temporal trends in the 
intervention effect, and will allow/test for a time-varying treatment effect via a functional logistic 
regression model, if needed (for which the original power calculations are conservative).21 
6.1.3. Analysis of Secondary Outcomes 
Secondary outcomes will be analyzed using similar procedures to the primary outcome. Comparisons 
between treatment arms will use logistic regression (dichotomous outcomes), linear regression 
(continuous outcomes), or survival analysis (survival time outcomes), as appropriate. 
6.2. Interim Analysis 
Since neonatal safety is a consideration in this study, we have chosen to use a group sequential design. 
Thus, in addition to the final analysis, we are planning on performing two interim statistical analyses 
during the course of this study. The purpose of the interim analyses will be to determine whether or not 
there is sufficient evidence of a difference between the treatment arms in the primary endpoint such 
that the trial should be discontinued prior to reaching the target accrual goal. The interim analyses will 
be performed after approximately 1/3 (200 subjects) and 2/3 (400 subjects) of the total required 
patients have completed their primary outcome. An additional safety review will be undertaken after 
1/6 (100 subjects) have completed their primary outcome. 
The primary outcome for the interim analyses will be the comparison of death/BPD between the 
treatment arms. This comparison will be accomplished by means of a simple generalized estimating 
equation (GEE) model for death/BPD versus treatment (since adjustment for multiples will be needed). 
An approximate O’Brien-Fleming boundary will be used at each interim look to calculate the nominal 
significance level to which interim p-values are compared.22 Using the O’Brien Fleming spending 
function, the three analyses (2 interim + final) should use the following incremental α values (0.0002, 
0.012, and 0.038) in order to achieve an overall α=0.05. 
Stopping criteria are for: 
(1) Clear superiority. Whether the experimental treatment is clearly inferior to standard therapy. For 
these calculations, we trade off the power to detect a difference and the size of that difference. 
Assuming α=0.0002 for boundaries for the initial interim analysis when 200 children have been followed 
to completion, power is limited except to detect large reductions in outcomes of death and BPD. For 
example, power is approximately 0.81 to detect a reduction from 65% in the conventional therapy to 

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32.5% in the experimental therapy, a 50% relative reduction. For the second interim analysis, using 
α=0.012, power with 400 children followed is about 0.85 to detect an absolute reduction from 65% to 
40% in the risk of death plus BPD. Thus, early or premature stopping for superiority is unlikely, without 
dramatic improvement from experimental treatment.  
(2) Inferiority. Power is limited to identify inferiority of the experimental treatment, with 0.8 power to 
demonstrate a 15% point increase in the risk of outcome from 65% in the standard therapy to 80% in the 
intervention.  
(3) Futility. Early stopping based on futility of the primary outcome will not be considered independently 
of the secondary clinical and safety outcomes. In the event that the intervention arm has equivalent 
BPD/death rates to the standard care arm, it would still be clinically useful to know if the intervention 
improves any of the secondary outcomes (that are closer to the time of the intervention) or decreases 
the serious adverse event rate. 
(4) Safety.  
(a) Early stopping based on inferior safety and non-inferior efficacy must be based largely on descriptive 
data and close examination of adverse events. With 200 subjects per group at a second early stopping 
review, and assuming that the experimental therapy is actually no worse than conventional care, 
observed risk in the experimental group would have to be at most 0.5 (risk of death and BPD) to have 
80% power to show non-inferior efficacy (with alpha = 0.012).  
(b) To justify stopping for non-inferior efficacy and superior safety again will require a substantial 
observed improvement in the experimental arm at the second early stopping time.  
(c) Another safety outcome is the rate of pneumothorax, pulmonary interstitial emphysema (PIE), 
and/or other serious adverse events (that have been adjudicated as potentially relating to the 
intervention; see section 8.2.2). In order to minimize the risk, this safety outcome will be compared 
between treatment arms after 1/6 (100 subjects) have completed the primary outcome, as well as at the 
two planned interim analyses for the primary outcome (1/3 and 2/3), since we would not expect any 
statistically significant differences in the rate after 100 subjects (with O’Brien-Fleming alpha 0.000002). 
Instead, we will look for a clinically meaningful double the risk in the intervention versus standard care 
arms.   
In summary, given the projected number of patients to be enrolled, early stopping will be unlikely unless 
the observed effect of experimental care is clearly better or worse than standard care at the planned 
early stopping assessment times. 
The results of the interim analyses will be judged by the DSMC. This committee will act completely 
independently of the clinical investigators, including the Principal Investigators. However, the ultimate 
decision to stop the study will rest with the steering committee. 
Note: An adaptive design was not used for this study. The efficacy improvement was minor over the 
conventional design. 

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7. 
Trial Management 
Project and data management support will be provided by the research team at the Clinical Research 
Computing Unit (CRCU), and the staff statistician at Biostatistics Analysis Center (BAC). Both of these 
groups are under the direction of Drs. Ratcliffe (co-PI), and Localio. Initial stages of data management 
will be done by experienced clinical data managers (CDMs), database developers, , supported by 
computer system analysts, programmers, and information technology (IT) specialists. These persons will 
be responsible for data quality and timeliness, documentation of processes and procedures, and training 
of data management staff.  
Every effort will be made to monitor data collection and entry and to correct errors, inconsistencies, 
ambiguities, and omissions in real time. Data will be entered directly into a secure, backed-up, 24-hour, 
web-based database using electronic case report forms (CRFs) developed by CRCU staff with the 
assistance of project investigators and statisticians. Data entry screens will incorporate range and logical 
edit checks, both within and across forms. Data entry will be followed daily with manual and 
programmed checks and edits for errors and omissions. A data monitoring plan written before the start 
of data collection will serve as a reference guide for the development of case report forms (paper and 
electronic versions), data handling conventions, reporting, data dictionaries, supporting meta data, as 
well as project closeout activities, communication and coordination plans among the PIs, clinical teams, 
sites coordinators, and staff and faculty-level statisticians. 
7.1. Data Security 
Access to direct identifiers will be limited to staff who meet all relevant training requirements and are 
assigned to (or support) this project, and who must have access to these identifiers for purposes of 
quality control and monitoring. All other persons, including statisticians and investigators will be blinded 
to identifiers until such time as for reasons of safety or clinical care, those identifiers must be shared. All 
investigators, statisticians, and staff will have completed the HIPAA and Human Subjects Protection 
training. All data with identifiers will be stored on firewall-protected secure servers. 
7.2. Data Sharing 
It is required of investigators at the University of Pennsylvania that research results generated under 
sponsorship by NIH are made available to the scientific community and public in a timely manner. The 
primary method by which data are shared with the scientific community is through peer-reviewed 
publications and presentation at meetings. In addition data and results created from NIH supported 
research will be submitted to NIH in the annual progress reports required under the terms and 
conditions of this award. This study will also be registered with clinicaltrials.gov. 
At the end of the study, limited access to the data may be granted to investigators external to the 
project. Such requests must be authorized by the PIs and the steering committee of the trial. To 
facilitate requests, the DCC will provide fully annotated final analytic datasets used to support published 
results. Such files will not contain any information on human subjects that could be used for their 

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identification. Depending on the type of request sharing of unpublished data may require a data sharing 
agreement, which will stipulate the conditions of their use. 
7.3. Data Safety Monitoring Committee (DSMC) 
A data monitoring safety committee (DSMC) will be established to: (1) protect all study patients, (2) 
safeguard the interests of all study patients, (3) monitor the overall conduct of the trial, (4) advise the 
investigators in order to protect the integrity of the trial, and (5) supervise the conduct and analysis of 
all interim analyses. To this end the DSMC will receive regular reports from the trial on any injuries or 
adverse events, any developments that jeopardize the continued success of the trial, and data by which 
to accomplish the evaluation of pre-determined early stopping rules.23  All Serious Adverse Events will 
be sent within 72 hours to the DSMC; reports of adverse events and recruitment will be sent monthly; 
demographics will be included with the interim and final safety and efficacy analyses.  
Two interim statistical analyses are planned during the course of this study. The primary endpoint to be 
used for efficacy and safety evaluation is the rate of Death or BPD at 36 weeks gestation age. The 
primary hypothesis to be tested is that the treatment therapy results in a decreased event rate.  A 
secondary safety outcome to be evaluated is the rate of serious adverse events (SAEs) between the two 
groups. Interim analyses will be performed by the project statisticians, independently from the trial 
leadership. The results of the interimum analyses will be provided to the DSMC. Additionally, the code 
used to produce the analyses will be provided to the DSMC biostatistican for independent, secondary 
verification of the results. 
7.3.1. Composition and Function of the DSMC 
This is an investigator-initiated study sponsored by the Pregnancy and Perinatology Branch of the 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).  
The NICHD scientists (T. Raju and M. Willinger) will receive AEs and SAEs and assure that they are 
sent to the Chair of the DSMC.  Dr. Raju will participate during the open segment of the DSMC 
meeting. Dr. Willinger will sit on the DSMC, but will not be a voting member. In addition, Dr. Raju 
(Chief, Pregnancy and Perinatology Branch, NICHD) retains close contacts with  investigators. but will 
not be a voting member.  
A DSMC has been appointed to work closely with the NICHD using NIH operating rules. There are no 
conflicts of interest with these individuals, who are not research collaborators of, and are at separate 
institutions from the investigators. 
The already named members of the DSMC are: 
Chair: Dr Alan Jobe 
Professor of Pediatrics, University of Cincinnati, whose primary 
focus is care of the newborn lung. 

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Members:  
Dr John Kattwinkel 
Emeritus Professor of Pediatrics, Division of Neonatology, 
University of Virginia, whose primary focus is evidence-based 
practice in neonatal resuscitation.  
Dr Elizabeth Thom 
Center Director of the Biostatistics Center at George Washington 
University, and Principal Investigator of the Data Coordinating 
Center for the NICHD Maternal-Fetal Medicine (MFM) Network, 
whose biostatistical expertise is in the conduct of multi-center 
clinical trials.  
Dr. Jonathan Fanaroff 
Associate Professor of Pediatrics, Case Western Reserve University 
School of Medicine, whose primary focus is ethics of neonatology 
research. 
Dr. Marian Willinger 
(Non-voting member) Program Scientist/Medical Officer, is also 
appointed to the Board to ensure co-oversight by the NICHD. 
All members of the DSMC are completely independent of the study and the PIs and will be required 
to sign documentation to this effect. The DSMC will conform to the recommended standards of the 
NIH (http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm). 
It will be the responsibility of the trial investigators to notify the IRB or IRBs involved of any issues 
that are relevant to patient safety or to early stopping of the study. The executive committee will 
discuss with the DSMC how frequently to review sites at the start-up phase to ensure safety, consent 
and enrollment. The DSMC will have at least one annual in-person meeting and teleconferences, as 
necessary, organized by the Data Coordinating Center (DCC). 
In brief the Committee will: 
• Review the research protocol, review model informed consent documents, and plans for data 
and safety monitoring, including all proposed revisions;  
• Review methodology used to help maintain the confidentiality of the study data and the 
results of monitoring by reviewing procedures put in place by investigators to ensure 
confidentiality; 
• Monitor study design, procedures and events that will maximize the safety of the study 
participants and minimize the risks; 
• Evaluate the progress of the study, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, 
performance of the study site(s), and other factors that may affect study outcome; 

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• Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the 
participants or the ethics of the studies; 
• Review serious adverse event documentation and safety reports and make recommendations 
regarding protection of the safety of the study participants. 
The DSMC is fully empowered to require any other specific changes to the trial (pertaining to patient 
safety and trial feasibility issues) prior to any local IRB submissions and prior to any start to 
enrollment. As is usual in such studies, the Steering Committee has the final responsibility for the 
trial and is the final seat of decisions. 
The DSMC deliberations will summarize topics discussed, recommendations made and will be signed 
by the board chair. All participating sites and their site PIs will receive a sanitized summary of board 
recommendations, to be forwarded to the IRB of each site.  
Any potential and actual Conflicts of Interest (COI) for board members will be reviewed and 
managed appropriately. 
8. 
Research Ethics 
8.1. Consent Options 
We will obtain an antenatal consent of parents of likely eligible infants 230-266 GA, who may be likely to 
conform to the inclusion and exclusion criteria. In this case a log will be maintained of all screened 
mothers-infants indicating who are eligible and which enrolled. 
We recognize that there are are serious personal burdens to mothers, practical difficulites, and finally, 
serious scientific concerns arising from the antenatal consent process. These are summarized as follows:  
Firstly; there is already an additional burden to distraught mothers who have been informed that they 
are at risk of preterm delivery. This is a difficult time to absorb the message that a possible 
randomization will be performed on their high-risk infant. Moreover, some of these these mothers may 
not even, in fact end up delivering an eligible baby. This is because threatened preterm delivery is an 
imprecise diagnose whereby approximately 50% of mothers may not in fact deliver until after 26 +6/7 
weeks. Data for this is shown in Rich W et al17, 18, and we discuss its implication for selection bias in the 
text below.  
Secondly, there is a limited time whereby parents can process and consider an informed consent process 
as can be seen from a detailed analysis of administration of antenatal corticosteroids in the Hospital of 
University of Pennsylvania study, which found the following:  
“Median time from presentation to delivery in those who received 1 dose (n= 85) 
was 7.96 hours (IQR, 4.1-17.3). In those who did not receive ANCS (n=64), the 
median time from presentation to delivery was 1.27 hours (IQR, 0.53-2.42; P 

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<.0001). Sixty-two percent of those who received only 1 dosILCS delivered in <12 
hours after the initial presentation. Of the 64 patients who did not receive ANCS, 
18.7% (n =12 women), 21.8% (n =14 women), 21.8% (n =14 women), and 37.5% 
(n=24 women) delivered at<30 minutes, 30-59 minutes, 60-120 minutes, and 
>120 minutes after presentation, respectively.”  In addition when comparing 
mothers who had two doses of ANCS to those who had none or only one dose, a 
dose response relationship is seen  such that the latter have a much higher 
proportion of infants < GA 30 weeks.24  
Finally, there is a serious potential for selection bias of the antenatal consent process, as noted by Rich 
W, et al.17, 18  This paper outlines the major problems of generalizabilty, and it is acknowledged by the 
authors of the SUPPORT trial that this has affected its findings.2  Nonetheless, after careful discussion 
with the IRB, we will adopt the full informed antenatal consent procedures. This is largely because of the 
uncertainty surrounding the currrent point estimates of potential risk. This is discussed in detail below. 
8.1.1. Consent Approach and Consent Form for Families  
The diagram below explains the practical sequence of events.  

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8.2. Risks of Study Participation 
The main risk of this maneuver is occurence of pneumothorax (air-leak). [Pneumothorax is the most 
serious of the spectrum of air-leaks. However we will also track Pulmonary interstitial Emphysmea (PIE) 
as potential complications (see section 9.2.3)]. While this risk is described in relation to the experimental 
procedure (Sustained Inflation), it is also encountered as a potential risk of any delivery room 
resuscitation. It is therefore explicitly acknowledged as a risk in the Newborn Resuscitation Program 
(NRP) teaching manual of the American Academy of Pediatrics and the American Heart Association 6TH 
Edition 2011; Editor J.Kattwinkel.4 [Page numbers in the next paragraph refer to this text]. It is relevant 
that all care-givers whether in the USA, Canada, Europe or Australia (where the SAIL recruiting sites are) 
are required to have successfully completed an NRP course or equivalent, in order to deliver care to 
these infants.  
The main predisposing etiological factor for pneumothorax is widely acknowledged to be the amount of 
airway pressure delivered to the lungs. As written in the NRP Guideline:  
“inadvertent high-inflating pressures being delivered to the patient may result in a 
pneumothorax” p.82;  
“high pressure may be generated in the baby and cause a pneumothorax or other 
air-leak” p.117;  
“Sufficient pressure to achieve a rise in heart rate and adequate ventilation should 
be provided, but excessive inflation pressure or too much CPAP can… create a 
pneumothorax” p.277. 
NRP also therefore has to proffer a standard treatment for pneumothorax which is outlined in 
considerable depth.  
Accordingly, the NRP recommends that there be pressure limits on the degree of inflation to be used 
during resuscitation of these infants:  
“If positive pressure ventilation is required, use the lowest inflation pressure 
necessary to achieve an adequate response. An initial inflation pressure of 20 to 
25 cm H2O is adequate for most preterm newborns… if you still not have any 
chest movement, you may need to increase the ventilating pressure cautiously..” 
p. 276.  
These suggested pressures are themselves a revision downwards from the original pressures stated by 
the NRP Guidelines of 2006.  
It is important therefore to note that the current NRP recommended range of peak pressure, is actually 
no different from that being applied at the airway by the sustained inflation maneuver in the current 
study. The first SI given is of a pressure of 20 cm H2O and the second is a pressure of 25 cm H2O.  

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Finally, in the randomized studies to date there has not been any increase in serious outcomes, like 
death rates, from the sustained inflation maneuver. However, in regard to the main potential risk to be 
discussed, we tabulate below the conflicting data on the rates of airleak in these studies.  
Risks of air-leak in randomized studies where two groups can be compared 
Study 
Rates of pneumothorax in control 
group using standard NRP 
Rates of pneumothorax in 
Sustained inflation group 
P values reported 
Lindner 2005 
4/30 (13%) 
3/31 (10%) 
Ns 
Te-Pas 2007 
7/103 (7%) 
1/104 (1%) 
0.069 
Lista Unpublished 2013 
(private communication) 
2/124 
8/126 
0.102 
 
Nonetheless, the point estimates for risk are based on insufficient data to enable a precise estimate. 
Therefore this risk is explictly discussed in the consent form.   
There may be unforeseen risks that may accompany the presence/treatment for a pneumothorax such 
oxygen desaturation, hypotension, bradycardia.  These unforeseen risks are possible in standard of care 
NRP guidelines as well as the sustained inflation arm of the study.  
8.3. Data Confidentiality 
All named study PIs at the US sites, and their research coordinators are CITI certified in conduct of 
clinical trials, as a requirement of their participation in any study. We will encourage those at the 
international sites to do the same. The basic rights of study participants will be respected and 
maintained by the investigators and by all who are involved in the collection or processing of individually 
identified data. All data collection and processing procedures are designed to protect individual rights 
and to comply with all applicable laws and ethical principles including confidentiality. Among the rights 
that must be protected are:  
 the right to informed consent, which requires that prospective participants in a research project 
and, if needed, their family members, be provided adequate information about the potential 
risks, benefits, and requirements of participation so that each can make an informed decision 
about participation 
 the right to decline, which requires that prospective participants be fully informed that their 
participation is completely voluntary, that they may withdraw at any time, that access to 
adequate health care will be provided whether or not they participate in the research, and that 
they may refuse to answer any question  
 the right to privacy, which requires guarantees of confidentiality of information and other 
specific protection as specified in the Privacy Act of 1974. 
The basic rights of study participants will be respected and maintained by the investigators and by all 
who are involved in the collection or processing of individually identified data. Our data collection and 
processing procedures are designed to protect individual rights and to comply with all applicable laws 

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and ethical principles. All staff who conduct or support research involving human subjects are required 
to undergo training on the protection of human subjects in research. 
We do not mandate any additional blood sampling, thus not departing from the standard practice of the 
NICU. Minimizing risks from procedures used to collect data is the responsibility of the clinical centers 
and the DCC, although procedures to minimize risk will be described in the study protocols and include 
medical management common for this study population. Confidentiality procedures for subject data will 
be established by the trial investigators before data are transferred to the DCC. All subject-identifying 
data will be kept solely at the clinical centers.  
The data collection forms will include unique study ID numbers only and basic demographic data as 
participant identifiers. Thus, the files maintained at DCC will contain limited identifying information and 
protect subject confidentiality. Safeguards are in place to greatly decrease the chances that 
characteristics of a case can be linked to the individual participating in the study.  
The DCC will receive subject data from the clinical centers identified by a study ID only and will never 
have contact with the subjects. All procedures related to DCC activities, including data transmission and 
data security procedures, are reviewed and approved by the DCC IRB prior to receipt of any study data 
at U Pennsylvania.  
At select sites, we will obtain video recordings of the infant resuscitation in order to assess adherence to 
the study treatment algorithm and to perform assurance for the RFM data processing.  
At many SAIL study sites, video recordings are standardly made during newborn resuscitation for quality 
improvement and audit, educational and research purposes. Each site will be responsble for obtaining 
IRB approval at their own site, and parental consent to allow short-term viewing and analysis of these 
videos for the SAIL trial.  
As detailed in the MOP, video recordings are used as quality assurance during the data processing for 
the RFM. Video files provide a method to clearly identify actions such as mask repositioning or 
spontaneous breathing, and they improve interpretation of respiratory waveforms under these 
conditions.  
Once generated, the videos will be labeled under the SAIL identifier and securely transferred to the 
UPenn DCC. All videos will be securely stored under the SAIL identifier at the DCC. Once the videos are 
reviewed for all research-related activities, they will be destroyed within 18 months at the SAIL DCC.  
9. 
Regulatory Oversight  
All clinical centers and the DCC have IRB committees that convene on a fixed schedule every month to 
review protocols and associated informed consent forms and data collection procedures for all research 
to ensure that they are in compliance with all applicable human subject regulations. IRB approval must 
be granted prior to beginning any study, and study progress and procedures must be reviewed by the 
IRB at least annually.  

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Potential subjects or their legal guardians must be fully informed about the details of any research study 
in which they are considering participation and what their involvement will entail. Specific consent forms 
are developed for each protocol and reviewed and approved by the IRBs at the DCC and at each clinical 
center. The DCC reviews forms used at the sites to ensure that essential elements of consent are 
presented and comply with federal law. 
All US clinical centers and the DCC have Federal wide Assurance (FWA) by the Office for Human Research 
Protections (OHRP) of the Department of Health and Human Services (HHS). This FWA is an agreement 
between each center, DCC and the U.S. government that all research with human subjects will be 
conducted according to appropriate federal regulations and allows us to undertake its own Institutional 
Review Board (IRB) review and monitoring of research with human subjects. Each institution 
participating in the trial holds an FWA, which ensures that the institution’s human research activities, 
overseen by their regulatory authorities, comply with the requirements set forth in 45 CFR 46, as well as 
the terms of Assurance. The DCC is responsible for obtaining appropriate clearances at our institution 
with respect to HIPAA and Human Subjects Research regulations and verifying similar clearances at the 
clinical centers.  
Trial study procedures are subject to the approval of the IRBs at the participating clinical centers and the 
DCC. For this trial, the protocol, informed consent (IC), and other study documents used at each center 
must be reviewed and approved by the respective IRBs and the DCC before the study is initiated. The 
IRBs monitor the research process to ensure that the procedures for protecting human subject rights are 
followed. Every protocol is reviewed by each IRB at least annually. Each IRB reviews SAE reports and 
approves all proposed changes to a research protocol before any changes are implemented. If 
necessary, the IRBs will mandate changes needed to protect the rights and welfare of human subjects or 
suggest solutions for problems that arise during a project.  
After IRB approval, infants eligible for the trial will be identified by the clinical center PI or study staff 
from among the infants who are cared for in the Neonatal Intensive Care Units. The PI or their staff will 
explain to the parents (1) consent forms that have been specifically written to address the nature, 
duration, and purpose of the study; (2) means by which it is to be conducted; (3) possible benefit or lack 
of benefits; (4) potential risks, hazards, and discomforts; and (5) possible alternative procedures. Specific 
decisions regarding the operational details of how consent will be sought (including the timing and the 
level of details presented regarding various aspects of the study) are made at the level of each clinical 
center under the guidelines of their local IRBs and practice policies and traditions.  
NICHD will defer to local IRB ruling for the conduct of the trial at all the clinical centers. Should a local 
IRB determine safety issues and require actions, including any related to suggested changes to the 
consent form, the local center research staff (investigator/coordinator) will notify the DCC, the NICHD 
Program Scientist. NICHD will direct the DCC in further action. Note that any changes to the protocol 
itself (directed either by any IRB or the DSMC) will require discussion and approval by the trial 
subcommittee and NICHD. The DCC will maintain all communications between the clinical center(s) and 
NICHD through resolution of all IRB issues.  

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9.1. Conflict of Interest 
We will ensure that no member appointed to the DSMC has a conflict of interest, and they will be 
required to sign to that effect. No one on the study team including the steering committee of the trial, 
has any financial interests related to resuscitation devices,nor do they act as consultants to any delivery 
room based commercial agencies. 
9.2. Collecting and Reporting Adverse Events 
A comprehensive manual of procedures will include a detailed section about reporting adverse events so 
that this is done uniformly across the sites. The trial will adhere to standard adverse event definitions as 
follows: 
9.2.1. Adverse Events (AE) 
“Adverse event is defined as any reaction, side effect, or untoward event that 
occurs during the course of the clinical trial associated with the intervention, 
whether or not the event is considered related to the treatment or clinically 
significant. A new illness, symptom, sign or clinically significant laboratory 
abnormality or worsening of a pre-existing condition or abnormality is considered 
an Adverse Event”. 
Adverse events will be monitored during the study to ensure timely detection of events that may 
affect safety or continued participation. In this trial, this extremely high-risk and fragile population 
will each experience expected and unexpected adverse events. Adverse events and their relationship 
to study, severity, time of experience, expectation, actions taken to resolve the event and final 
outcome will be recorded as documented in the medical record, or if reported by the NICU team 
even before documentation. These event rates will be part of reporting the final results of the study 
and for the DSMC safety monitoring. 
Secondary outcomes of interest in this trial that can be compared across the two treatment groups 
include: death; Bell Stage 2-3 necrotizing enterocolitis; periventricular leukomalacia or echodense 
lesions or ventriculomegaly; apnea mandating either caffeine or respiratory support; 
bronchopulmonary dysplasia; retinopathy of prematurity requiring intervention; and each 
component of the primary outcome (available only after the 22 to 26 month follow-up visit). Rates of 
these events, historically observed among similar extremely low gestation/birth weight infants, will 
be provided to the DSMC for comparison. Common, serious neonatal morbidities will also be 
collected. These include data on in-hospital growth, the incidence and severity of intraventricular 
hemorrhage, seizures, patent ductus arteriosus (PDA) and its treatment, nosocomial sepsis (and 
organisms), hearing impairment, and pneumothorax. 
9.2.2. Serious Adverse Events (SAE) 
The serious adverse event (SAE) definitions are listed below. Based on the premature infant 
population studied, the SAE categories of events that result in congenital anomaly/birth defect or 

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require intervention to prevent permanent impairment or damage (devices) do not apply when 
defining events. 
An adverse event or suspected adverse reaction is considered serious if in the review of the 
investigator or the sponsor, it results in any of the following: 
Death of Subject 
An event that results in the death of a subject. 
Life-Threatening 
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken. This does not include an event that would have been 
fatal if it had occurred in a more severe form. 
Prolongation of Hospitalization 
An event that prolongs the patient's hospital stay.  
Results in persistent or 
significant disability/incapacity 
An adverse event that  may result in a substantial disruption of 
the ability to conduct normal life functions, i.e., the adverse 
event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the infants body 
function/structure, physical activities and/or quality of life. 
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent Serious 
Outcome 
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, prolongation 
of hospitalization). An example of such events would be an 
allergic bronchospasm requiring intensive treatment. 
Expedited Serious Adverse Events (SAE) 
The sponsor NICHD will determine if individual serious adverse events a) meet the criteria for 
expedited reporting and b) ensure that they are promptly reported to the DSMC.  
Unexpected Adverse Event 
An unexpected AE is defined as any adverse event, the specificity or severity of which is not listed in 
the study protocol, product inserts, or informed consent document. 
Attribution is the determination of whether an adverse event is related to a medical treatment or 
procedure. This will be determined by the site PI and study team, according to the basis of the below 
classification:  
1) Definitely 
2) Probably 
3) Possibly 

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4) Unlikely 
5) Unrelated 
9.2.3. Clinical Events Defined 
The chart below shows the specific clinical events that are defined as serious for the SAIL Study and 
the reporting requirements established for the clinical sites: 
Adverse Event definitions: 
Time Frame 
Oxygen requirement of Fi02 ≥ 40% for 2 hours or more 
Within the first 48 hours post delivery 
 
Grade 1 or 2 IVH 
Head ultrasound findings with the first 10 
days of life (report based only) 
Infant requiring > 30% Oxygen or mechanical support 
Respiratory support assessment at day of 
life 28 
 
Serious Adverse Event definitions: 
Time Frame 
Death 
Within the first 48 hours post delivery 
Administration of epinephrine  or use of chest 
compressions  
Within the first 48 hours post delivery 
 
Pneumothorax, pulmonary interstitial emphysema (PIE) 
and pneumopericardium. These will be supplemented by 
data on: 
         a) any chest tube in-situ post DR 
         b) need for new chest tube after arrival in NICU 
Radiographic evidence within the  
first 10 days of life  
Grade 3 or 4 IVH 
Head ultrasound findings with the first 10 
days of life (report based only) 
 
9.2.4. Unanticipated Problems 
An Unanticipated Problem is defined as any incident, experience, or outcome that meets all of the 
following criteria: 
1) Is not expected in terms of nature, severity, or frequency in relation to (a) the research risks 
that are described in the IRB-approved research protocol and informed consent document; 
Investigator’s Brochure or other study documents, and (b) the characteristics of the subject 
population being studied; and 
2) Is related or possibly related to participation in the research; and 
3) Places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously know or recognized. 
9.2.5. Adverse Event Management and Reporting 
If an adverse event meets any of the criteria listed above of Serious, Unexpected and at least 
Possibly Attributable to the study therapy or intervention, it will be reported by study team at the 
recruiting site to the NICHD, the Data Coordinating Center (DCC), and the local IRB (per site specific 

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IRB procedures) as a serious adverse event via the Medwatch Safety Reporting Form 3500A or a 
form that mimics it.  
Adverse Event/Serious Adverse Event forms will be completed by site research staff (investigators 
and/or coordinators) for each reportable (as defined by protocol ) adverse event that infants may 
experience from the time of randomization through the predefined intervention and/or events 
monitoring period. Events will be documented by clinical site staff using case report forms (CRF), 
reviewed and signed by the site investigator for accuracy and completeness then entered into the 
specified Data Management System (DMS) as instructed in the manual of procedures.   
1. A preliminary SAE alert must be submitted within 24 hours of first knowledge of the event. 
2. A more complete SAE report should be submitted (on Medwatch form 3500A or a similar 
form developed by the DCC) within 72 hours.  
3. A final report must be submitted by the site to the DCC within one week, including when 
applicable, autopsy findings.  
4. The final report will then be submitted to the DSMC Chair for independent adjudication of 
relatedness to the intervention.  
The Program Scientist at NICHD and/or the DCC will determine whether expedited DSMC reviews are 
necessary. The DSMC can recommend further action and the DCC will be responsible for notification 
to the local site team and NICHD. NICHD may request the DCC notify required parties through 
established communication mechanisms via technical memos. 
Reporting to the Food and Drug Administration will not be required for this trial as it involves no new 
drug or device intervention mandating an IND/IDE. 
10. 
Synopsis 
It is expected that trial completion in 12 sites will take 5 years, including 2.5 years of recruitment.  
This project has huge public health implications due to large burden from death and BPD in this 
population. The study intervention (SI) is poised to reduce this burden, and the trial would be at the 
‘right time’, for a not-yet established therapy with promising pilot data. Moreover the potential benefits 
are lifelong, if the strategy is successful. In addition to the outstanding track record and expertise of the 
US based co-PIs, the overseas co-PIs are essential for successful trial completion. The key benefits of the 
foreign sites include content expertise in DR research and sustained inflation. Most of the animal and 
human data on this novel technique comes almost exclusively from Europe and Australia. Similar large 
scale RCTs (TIPP, CAP, PINT) have been completed internationally. In addition PD is a member of ILCOR, 
confirming the critical importance of the question and guaranteeing translation to clinical practice. We 
submit that the involvement of all these highly committed international sites, but under US leadership, 
and in collaboration with the US sites – can only further promote the currently high profile of neonatal 

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trial research led by the US. A deserved field to further this is Delivery room resuscitation. This has been 
for too long, a neglected area for randomized trial evidence based medicine.  
11. 
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