The Bronchopulmonary Dysplasia Saturation TARgeting (BPD STAR) Pilot Trial
Phase: NA
Conditions: Bronchopulmonary Dysplasia, Chronic Lung Disease of Prematurity, Chronic Lung Disease
Sponsor: Children's Hospital of Philadelphia

 
 
Clinicaltrials.gov Document Cover Page 
 
Protocol Title: 
 
BPD Saturation TARgeting (BPD STAR) 
 
Document Date: 
 
3/5/21 
 
NCT Number: 
 
NCT03385330 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
ii 
 
Title: 
 
The Bronchopulmonary Dysplasia Saturation TARgeting Pilot Trial 
Short Title 
 
BPD STAR Pilot Trial 
 
 
 
Regulatory 
Sponsor: 
 
Thrasher Research Fund 
eIRB 
Number: 
 
IRB 17-014522 
 
Original Submission: 12/21/2017 
Revision Date: 10/19/2018 
Revision Date: 2/20/2018 
Revision Date: 1/16/2019 
Revision Date: 3/5/2018 
Revision Date: 4/4/2019 
Revision Date: 4/22/2019 
Revision Date: 5/31/2019 
Revision Date: 8/6/2019 
Revision Date: 1/27/2021 
 
 
 
 
 
 
 
 
 
 
Study Principal Investigator 
Sara B. Demauro, MD MSCE 
Assistant Professor of Pediatrics 
University of Pennsylvania Perelman School of Medicine 
The Children’s Hospital of Philadelphia 
Division of Neonatology, 2nd Floor Main Building 
3401 Civic Center Boulevard 
Philadelphia, PA 19104 
Phone 215-913-8931 
email: demauro@email.chop.edu 

 
 
 
 
 
 
 
 
iii 
 
 
 

  
 
 
 
 
 
 
 
iv 
TABLE OF CONTENTS 
Table of Contents ......................................................................................................... iv 
Abstract ...................................................................................................................... viii 
Protocol Synopsis ......................................................................................................... ix 
Table 1: Schedule of Study Procedures ....................................................................... 13 
Figure 1: SCHEMATIC OF STUDY PROCEDURES ..................................................... 1 
1 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 2 
1.1 
INTRODUCTION ........................................................................................................................................ 2 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ........................................ 2 
1.3 
RELEVANT LITERATURE AND DATA .......................................................................................................... 2 
1.4 
COMPLIANCE STATEMENT ........................................................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 4 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................ 4 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 4 
3 
INVESTIGATIONAL PLAN ............................................................................................................... 4 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ...................................................................................................... 4 
3.1.1 
Screening- Baseline ......................................................................................................................... 4 
3.1.2 
Phase 1 – Inpatient monitoring ..................................................................................................... 5 
3.1.3 
Phase 2 – Outpatient monitoring ................................................................................................... 5 
3.1.4 
Phase 3 – 3 and 6 month corrected age outcomes assessment ..................................................... 6 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ............................................................................ 6 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ........................................................................ 6 
3.3.1 
Duration of Study Participation ..................................................................................................... 6 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .............................................. 7 
3.4 
STUDY POPULATION ................................................................................................................................. 7 
3.4.1 
Inclusion Criteria ............................................................................................................................ 7 
3.4.2 
Exclusion Criteria ........................................................................................................................... 7 
4 
STUDY PROCEDURES ...................................................................................................................... 8 
4.1 
INPATIENT SCREENING AND ENROLLMENT ................................................................................................ 8 
DATA ELEMENTS TO BE COLLECTED ARE LISTED IN SECTION 5. ......................................................................... 8 
4.2 
INPATIENT STUDY PROCEDURES AND DATA COLLECTION .......................................................................... 8 
DETAILS OF RANDOMIZATION ARE PROVIDED ABOVE IN SECTION 3.2,  DATA ELEMENTS TO BE COLLECTED 
AFTER ENROLLMENT AND DURING THE INPATIENT PHASE ARE LISTED IN SECTION 5. ........................................ 8 
4.3 
OUTPATIENT STUDY PROCEDURES AND DATA COLLECTION ...................................................................... 8 
4.3.1 
Oxygen Saturation Monitoring ...................................................................................................... 8 
4.3.2 
Study outcomes and safety data ..................................................................................................... 9 
4.3.3 
End of Study .................................................................................................................................... 9 
4.4 
UNSCHEDULED VISITS ............................................................................................................................ 10 
4.5 
CONCOMITANT MEDICATION ................................................................................................................. 10 
4.6 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................... 10 
4.6.1 
Early Termination Study Visit ..................................................................................................... 10 
5 
STUDY EVALUATIONS AND MEASUREMENTS .......................................................................... 10 

  
 
 
 
 
 
 
 
v 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ..................................................... 10 
5.1.1 
Medical Record Review: Screening ............................................................................................. 10 
5.1.2 
Inpatient Data Collection ............................................................................................................. 11 
5.1.3 
Discharge Data Collection ............................................................................................................ 11 
5.1.4 
Outpatient Data Collection .......................................................................................................... 12 
5.2 
EFFICACY EVALUATIONS ........................................................................................................................ 12 
5.2.1 
Efficacy Evaluations: Oximetry ................................................................................................... 12 
5.2.2 
Efficacy Evaluations: Clinical ....................................................................................................... 13 
5.3 
SAFETY EVALUATION ............................................................................................................................. 14 
6 
STATISTICAL CONSIDERATIONS ................................................................................................. 14 
6.1 
PRIMARY ENDPOINT ............................................................................................................................... 14 
6.2 
SECONDARY ENDPOINTS ........................................................................................................................ 14 
6.3 
STATISTICAL METHODS .......................................................................................................................... 14 
6.3.1 
Baseline Data ................................................................................................................................. 14 
6.3.2 
Efficacy Analysis ........................................................................................................................... 14 
6.3.3 
Safety Analysis .............................................................................................................................. 15 
6.4 
SAMPLE SIZE AND POWER ...................................................................................................................... 15 
6.5 
INTERIM ANALYSIS ................................................................................................................................. 15 
7 
STUDY INTERVENTION ................................................................................................................ 16 
7.1 
DESCRIPTION .......................................................................................................................................... 16 
8 
SAFETY MANAGEMENT ................................................................................................................ 16 
8.1 
CLINICAL ADVERSE EVENTS ................................................................................................................... 16 
8.2 
ADVERSE EVENT REPORTING ................................................................................................................. 16 
8.3 
DEFINITION OF AN ADVERSE EVENT ....................................................................................................... 16 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ................................................................................ 17 
8.4.1 
Relationship of SAE to intervention ............................................................................................ 17 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS .......................................... 17 
8.5.1 
Follow-up report ........................................................................................................................... 18 
8.6 
MEDICAL EMERGENCIES ......................................................................................................................... 18 
9 
STUDY ADMINISTRATION ........................................................................................................... 18 
9.1 
TREATMENT ASSIGNMENT METHODS ..................................................................................................... 18 
9.1.1 
Randomization .............................................................................................................................. 18 
9.1.2 
Blinding ......................................................................................................................................... 18 
9.2 
DATA COLLECTION AND MANAGEMENT ................................................................................................ 18 
9.3 
CONFIDENTIALITY .................................................................................................................................. 19 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS ...................................................................................... 19 
9.4.1 
Data and Safety Monitoring Plan ................................................................................................. 19 
9.4.2 
Risk Assessment ............................................................................................................................ 20 
9.4.3 
Potential Benefits of Trial Participation ...................................................................................... 20 
9.4.4 
Risk-Benefit Assessment .............................................................................................................. 21 
9.5 
RECRUITMENT STRATEGY ....................................................................................................................... 21 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ................................................................ 21 
9.6.1 
Waiver of Assent ........................................................................................................................... 22 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ........................................................................................................... 22 
10 PUBLICATION ................................................................................................................................ 22 

  
 
 
 
 
 
 
 
vi 
11 REFERENCES .................................................................................................................................. 23 

 
 
 
 
 
 
 
 
 
 
vii 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
 
 
NICU 
BPD 
SpO2 
IH 
CA 
PMA 
 
Neonatal Intensive Care Unit 
Bronchopulmonary dysplasia 
Oxygen saturation 
Intermittent hypoxemia 
Corrected age 
Postmenstrual age 
ROP 
ATS 
 
Retinopathy of Prematurity 
American Thoracic Society 
NC 
 
Nasal Cannula 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
viii 
ABSTRACT 
Context: Bronchopulmonary dysplasia (BPD), or chronic lung disease of prematurity, is 
most commonly defined as oxygen dependence at 36 weeks postmenstrual age (PMA). 
BPD affects nearly half of surviving extremely preterm (<28 weeks gestational age) 
infants, and the incidence of BPD has increased over time. Infants with BPD face more 
than doubled odds of death after 36 weeks PMA or disability at 5 years compared to 
preterms without BPD. BPD is associated with abnormal lung function throughout 
childhood and significantly increases health care costs. Cognitive and respiratory 
outcomes are closely linked throughout the life course; thus, optimal long-term 
management of BPD during infancy may ultimately improve cognitive outcomes of this 
high-risk population.   
Objectives: The primary objective is to compare the incidence of intermittent hypoxemia 
(IH) and total duration of hypoxia up to 6 months corrected age (CA) among infants with 
BPD randomized to higher versus lower oxygen saturation (SpO2) target ranges. The 
secondary objective is to describe clinically relevant outcomes over the first 6 months in the 
two study groups. 
Study Design: This is a randomized pilot clinical trial. Since the two SpO2 target groups in 
the current trial represent the currently accepted range of clinical practice, neither group is 
labeled as “intervention” or “control.” 
Setting/Participants: In collaboration with Hospital of the University of Pennsylvania (HUP) 
and its affiliate hospitals, potential participants will be enrolled from the Neonatal Intensive 
Care Units (NICUs) at The Children’s Hospital of Philadelphia (CHOP), Pennsylvania 
Hospital (PAH) and HUP. We will enroll up to 50 infants who were born <30 weeks and 
who remain on respiratory support at 34-44 weeks PMA (ie, have moderate or severe BPD). 
CA.  
Study Interventions and Measures: Enrolled infants will be randomized to higher or lower 
SpO2 target ranges (a target SpO2 of >=96% or 90-94%). The study intervention will begin 
in the hospital and will continue at home until 6 months. We will utilize 2- second sampling 
and averaging times and measure IH longitudinally throughout the study period in all 
participants regardless of home oxygen use. We define IH as SpO2<80% for >30 
seconds. Primary outcomes are incidence of IH and total duration of hypoxemia up to 6 
months CA. Specifically, these are measured as differences between the two groups in 
incidence of IH at 40 weeks PMA, 3 months CA, and 6 months CA and percent of 
recording time spent <80%, <85% and <90% SpO2 over the study period. Secondary 
outcomes are growth, feeding development, health-related resource utilization and 
quality of life. 
The study team will use novel technology to perform overnight continuous oximetry after 
discharge and until 6 months CA. These data will be transmitted wirelessly to the study 
team using a novel, compact and low-cost device, whenever relevant, supplemental 
oxygen will be titrated according to a study algorithm, in order to maintain study 
participants within the target SpO2 ranges.  

  
 
 
 
 
 
 
 
ix 
PROTOCOL SYNOPSIS 
Study Title 
The Bronchopulmonary Dysplasia Saturation TARgeting Pilot Trial 
Funder 
Thrasher Research Fund 
Clinical Phase 
Phase I (Pilot Study) 
Study Rationale 
Supplemental oxygen is a lifesaving therapy for premature infants 
and a common post-discharge treatment for BPD. There is limited 
evidence to guide the use of supplemental oxygen beyond the 
immediate newborn period. No controlled studies have described 
continuous oxygen saturation monitoring post-discharge for infants 
with established BPD or evaluated the safety and efficacy of 
reducing IH to improve outcomes of infants with established BPD. 
Study Objective(s) 
Primary  
• 
To compare the incidence of IH (SpO2 <80% for >=30 seconds) 
up to 6 months corrected age among infants with moderate or 
severe BPD randomized to higher versus lower SpO2 target 
ranges. 
Secondary 
• 
To explore clinically relevant outcomes over the first 6 months 
in the two study groups.  
Test Article(s) 
 
Preterm born infants who remain on respiratory support at 34-44 
weeks PMA will be randomized to higher or lower oxygen 
saturation target ranges, which will be maintained until 6 months 
corrected age.  Both of these target ranges are within the wider 
range commonly used in clinical practice. 
• For the lower target group our goal is to keep oxygen 
saturations between 90-94%. In hospital, inspired oxygen 
will be adjusted as needed to maintain target SpO2. 
Monitoring will continue after discharge, and whenever 
children are discharged on supplemental oxygen, oxygen 
flow will be titrated monthly according to a standardized 
algorithm. 
• For the higher target group our goal is to keep oxygen 
saturations greater than or equal to 96%. In hospital, inspired 
oxygen will be adjusted as needed to maintain target SpO2. 
Monitoring will continue after discharge, and whenever 
children are discharged on supplemental oxygen, oxygen 
flow will be titrated monthly according to a standardized 
algorithm. 
Study Design 
 
Randomized controlled pilot study. 

  
 
 
 
 
 
 
 
x 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Pre-term male or female infants born at <30 0/7 weeks 
gestation  
2. Current age 34 0/7 to 43 6/7 weeks postmenstrual age 
3. Diagnosis of moderate or severe Bronchopulmonary 
Dysplasia based on the NIH consensus definition 
4. Infant has never been discharged to home from the hospital 
Exclusion Criteria 
1. Congenital anomaly or oncologic process likely to affect 
growth or respiratory status 
2. Hemoglobinopathy or other blood disorder likely to affect 
oxygen saturations 
3. Contraindication to nasal cannula use (for example, severe 
nasal septal breakdown) 
4. Pulmonary hypertension requiring pharmacotherapy at the 
time of screening/enrollment 
5. Tracheostomy 
6.  Intubated during entire eligibility period 
Number Of Subjects  
50 enrolled (42 evaluable) between CHOP, HUP, and PAH 
Study Duration 
Each subject’s participation will last up to 8 months. The entire 
study is expected to last 3 years. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
1) Baseline/Screening: screening for eligibility and obtaining 
consent  
2) Phase 1: Inpatient  
3) Phase 2: Outpatient oxygen Saturation Monitoring (discharge to 6 
months CA) 
4) Phase 3: Outcomes assessment at 3 and 6 Months CA 
Efficacy Evaluations 
1. Oximetry 
2. Growth checks 
3. Developmental assessment 
4. Parent questionnaires  
Safety Evaluations 
1. Close supervision from study physician. 
2. All adverse events will be recorded and reported in accordance 
with CHOP and all other regulatory requirements. All adverse 
events and near misses will be discussed during monthly study 
team meetings to continually evaluate participant safety and 
prevent future adverse events. 
Statistical And 
Analytic Plan 
The primary endpoints are the incidence of IH (SpO2 <80% for 
>=30 seconds) and total duration of hypoxia up to 6 months CA 

  
 
 
 
 
 
 
 
xi 
among infants with BPD randomized to higher versus lower SpO2 
target ranges. 
All secondary endpoints in this pilot study are exploratory and 
descriptive.  The primary clinical outcome is growth in kilograms 
between 36 weeks PMA and 6 months CA.  In addition, the study 
will also report: 
• The change in other growth parameters - length (cm), weight for 
length, and head circumference (cm) - between 36 weeks PMA 
and 40 weeks PMA, 3 months CA, and 6 months CA. 
• Differences between groups on a standardized feeding 
questionnaire at 3 and 6 months CA. 
• Differences between groups in parent and child quality of life at 
3 and 6 months CA. 
• Differences between the groups in health care utilization at 3 
and 6 months CA. 
• Differences between the groups in development at 6 months CA. 
• Safety, assessed as differences in growth, re-hospitalizations, 
and any safety events at 3 and 6 months CA. 
 
DATA AND SAFETY 
MONITORING PLAN 
Data will be managed and stored in a password-protected database 
using REDCap (Research Electronic Data Capture). Only study 
team members will have access to the REDCap database for data 
entry under the supervision of and after training by the PI. Hard 
copies of data collection instruments will be stored in a locked 
cabinet in the PI’s locked office. Participants will be assigned a 
unique identifier that contains no protected health information 
(PHI). PHI will be coded as identifiable information in REDCap 
using REDCap’s built-in security features. Access to the identifiers 
of the coded data will be controlled by the PI and only study team 
members will have access to the electronic and paper data.  
 
The PI will be responsible for monitoring the data and safety of all 
participants. All study procedures will receive IRB approval prior to 
recruitment or enrollment of participants. In addition to the data 
management procedures outlined above, the PI will hold monthly 
study team meetings to evaluate the safety and progress of all 
research procedures. Standard procedures for all data collection 
methods will be reviewed at the start and periodically throughout 
the study. Data checks for errors will be performed prior to analysis. 
Adverse events and serious adverse events will be reported to the 

 
 
 
 
 
 
 
 
 
 
xii 
CHOP IRB and other regulatory authorities in accordance with 
federal and other relevant regulations. 

 
 
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
 
Study Activity 
Recruitment 
Phase & 
Screening 
Enrollment 
Phase 
 
 
Study Timeframe 
Baseline 
34-44 (weeks) 
Discharge Weekly after 
discharge 
Monthly 
after 
discharge 
3 
Months 
CA  
6 Months 
CA 
Pre-Enrollment Pool EPIC- 
CHOP/PENN/PAH 
X 
 
 
 
 
 
 
 
Medical Record Review 
X 
 
 
 
 
 
 
 
Conduct Eligibility Screen 
X 
 
 
 
 
 
 
 
Approach Families (Beginning 
34weeks, PMA) 
 
X 
 
 
 
 
 
 
Parental Consent 
 
 
X 
 
 
 
 
 
Participant Randomization 
 
 
X 
 
 
 
 
 
Weight, length, and head 
circumference are measured 
 
 
X 
 
 
 
X 
X 
Placement of SPO2 study 
monitors/ training with families 
 
 
 
 
 
 
 
 
 
Feeding questionnaire and diary 
 
 
 
 
 
 
X 
X 
Data from monitor are reviewed 
by study team and family is 
contacted if needed 
 
 
 
 
 
 
 
 
Feeding Questionnaire** 
 
 
 
 
 
 
X 
X 
ITQOL-SF47 (Parent/Child 
quality of life) ** 
 
 
 
 
 
 
X 
X 
Health care utilization data is 
collected 
 
 
 
 
 
 
X 
X 
Bayley Scales of Infant 
Development Screener 
 
 
 
 
 
 
 
X 
Participant Compensation. 
Payments issued 
monthly($50/visit; up to 6 
visits) 
 
 
 
 
 
X 
 
 
Weekly data transfers to CHOP 
Continuous over 6 months 

 
 
 
 
 
 
 
 
 
Adverse Event/Serious Adverse 
Event Assessment 
 
 
X 
X 
X 
 
X 
X 

 
 
 
 
 
 
 
1 
FIGURE 1: SCHEMATIC OF STUDY PROCEDURES 
 
 

 
 
 
 
 
 
 
2 
1 
BACKGROUND INFORMATION AND RATIONALE 
Bronchopulmonary Dysplasia affects up to half of very preterm infants, yet little is known about 
how this condition is best managed in the outpatient setting, especially in the time immediately 
following discharge from the neonatal hospitalization. The proposed trial will be the first study of 
oxygen saturation targeting for infants with established BPD and the first study to evaluate the 
efficacy and safety of home oxygen saturation targeting for this vulnerable population. 
1.1 Introduction 
Bronchopulmonary dysplasia (BPD) is most commonly defined as oxygen dependence at 36 weeks 
postmenstrual age. BPD affects nearly half of surviving extremely preterm (<28 weeks gestational 
age) infants, and the incidence of BPD has increased over time. Infants with BPD face more than 
doubled odds of death after 36 weeks PMA or disability at 5 years compared to preterms without 
BPD. BPD is associated with abnormal lung function throughout childhood and significantly 
increases health care costs. Cognitive and respiratory outcomes are closely linked throughout the 
life course; thus, optimal long-term management of BPD during infancy may ultimately improve 
cognitive outcomes of this high-risk population.   
Supplemental oxygen is a lifesaving therapy for premature infants; yet, there is limited evidence to 
guide the use of supplemental oxygen beyond the immediate newborn period. The American 
Thoracic Society (ATS) has been quite definitive in stating that “oxygen is increasingly viewed as a 
safe and relatively convenient means for maximizing growth and development” in infants with 
BPD. But supplemental oxygen also carries potential risk, as it is implicated in the causal pathway 
for morbidities such as retinopathy of prematurity (ROP). In addition, targeting high oxygen 
saturations (SpO2) with supplemental oxygen may be associated with increased pulmonary oxygen 
toxicity and decreased quality of life, without improving neurologic outcomes. In the absence of 
sound evidence to guide medical decisions, there is currently a significant variation in practice with 
regard to use of oxygen therapy in this population. No controlled studies have evaluated the safety 
or efficacy of supplemental oxygen for improving outcomes of infants with established BPD. This 
is a critical knowledge gap in neonatal and pediatric pulmonary medicine. This study will test 
whether targeting higher versus lower oxygen saturations in infants with BPD influences rates of 
hypoxemia and clinical outcomes during the first 6 months of life. 
1.2 Name and Description of Investigational Product or Intervention 
The intervention that will be tested in the current study is higher versus lower oxygen saturation 
target ranges for infants with established BPD. 
1.3 Relevant Literature and Data 
Several recently published randomized trials have compared oxygen saturation (SpO2) target ranges 
for extremely preterm infants immediately after birth, up to only 36 weeks PMA. These trials have 
differing methodology and conflicting results.(1-3) Two older trials compared SpO2 target ranges 
for slightly older preterm infants. The BOOST trial randomized 358 preterm infants who were 
oxygen dependent at 32 weeks to higher (95- 98%) or standard (91-94%) saturation target ranges. 
(4) Participants remained on the study intervention until oxygen was discontinued: a median of 2.5 
weeks in the standard target group and 5.7 weeks in  the  high  target group. Only about half of the 
infants still required supplemental oxygen at 36 weeks. The BOOST Trial did not demonstrate any 

 
 
 
 
 
 
 
3 
benefits associated with targeting higher SpO2 in this population. The STOP- ROP multicenter 
trial randomized 649 infants with pre-threshold retinopathy and a median SpO2 of <94% to 
conventional oxygen targets (SpO2 89-- 94%) and supplemental oxygen targets (96-99%). (5) 
These targets were continued for two weeks or until the infants met the ophthalmologic endpoint 
of the study, whichever occurred later. STOP-ROP was stopped early for futility and a loss of 
equipoise in favor of the high saturation arm. The adjusted odds ratio for progression to threshold 
retinopathy in the supplemental arm as compared to the conventional arm, which was the primary 
outcome of the trial, was 0.72 (95%CI 0.52-1.01). In these trials, there were no differences 
between the groups in growth at 36 weeks or 12 months (BOOST) or 2 months (STOP- 
ROP).(4,5) In summary, RCTs in the acute newborn period up to 36 weeks have conflicting 
results; and studies from 32-36 weeks show no benefit but potential harm. Crucially, no trials 
have compared the impact of prolonged SpO2 targeting for very preterm children with moderate or 
severe BPD after 36 weeks. 
Secondary analyses of a large randomized trial comparing higher versus lower SpO2 targeting for 
newborn extremely preterm infants(6) demonstrated that IH, and in particular events <80% for at 
least one minute, are common in this population between birth and at least 9-10 weeks of age.(7) 
The duration of time with SpO2 <80% is associated with the combined outcome of death after 36 
weeks or disability at 18 months, cognitive or language delay, motor impairment, and severe 
retinopathy of prematurity. Importantly, this effect is significantly stronger when IH occurs 9- 10 
weeks after birth than when it occurs earlier. While the neonatal community has been striving to 
minimize events in the weeks prior to discharge, these data force us to evaluate the value of 
reducing IH throughout infancy. It is unknown whether infants with BPD continue to have IH after 
36 weeks PMA or after hospital discharge, or whether ameliorating this with longer-term use of 
supplemental oxygen would improve outcomes of these high-risk infants.  IH is an important and 
novel therapeutic target in BPD, and may be a key component of decisions regarding safe and 
appropriate use and weaning of supplemental oxygen. 
A recent trial of late caffeine therapy enrolled infants who were at least 33 PMA and in room air.(8) 
The control group had an average of 8.4 episodes of intermittent hypoxemia (decline in SpO2 by at 
least 5% from baseline to <90% and lasting at least 5 seconds) per hour at 35 weeks PMA, which 
declined to 3.0 events per hour at 39 weeks PMA. The total time spent with saturations <90%, 
<85%, and <80% declined dramatically between 35 and 39 weeks. The clinical relevance of these 
more minor IH episodes and periods of hypoxia have not yet been demonstrated. 
Our study collaborators have developed a simple, low--cost device for the BPD STAR Trial that 
securely transmits oximetry data wirelessly from the home environment. This device will enable us 
to implement a novel approach to studying management and outcomes of BPD.  This study will 
provide critical data about whether infants with BPD continue to have IH after discharge; whether 
targeting higher SpO2 ameliorates IH; and whether this management strategy is associated with 
improved outcomes until 6 months of age.  
1.4 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of Philadelphia 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46 and the Good Clinical Practice: Consolidated Guideline approved by the 

 
 
 
 
 
 
 
4 
International Conference on Harmonisation (ICH). All episodes of noncompliance will be 
documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
assent, and will report unanticipated problems involving risks to subjects or others in accordance 
with The Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal 
requirements. Collection, recording, and reporting of data will be accurate and will ensure the 
privacy, health, and welfare of research subjects during and after the study.  
 
2 
STUDY OBJECTIVES 
The purpose of this study is to test whether targeting higher, as compared to lower, oxygen 
saturations reduces the incidence of IH and improves clinical outcomes for preterm infants with 
established BPD. 
2.1 Primary Objective 
The primary objectives of this study are to compare the incidence of intermittent hypoxemia 
(defined as: SpO2 <80% for >=30 seconds) and total duration of hypoxemia between 36 weeks 
PMA and 6 months corrected age among infants with BPD randomized to higher versus lower 
SpO2 target ranges. 
2.2 Secondary Objectives 
The secondary objectives are to describe clinically relevant outcomes over the first 6 months in the 
two study groups. These outcomes include quality of life, respiratory health-related resource 
utilization, feeding, and growth.  
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
The proposed study will be a randomized clinical pilot trial. Enrolled infants with moderate or 
severe BPD will be randomized to higher or lower oxygen saturation (SpO2) target ranges, 
which will be maintained until 6 months corrected age.   
The two SpO2 target groups represent the currently accepted range of clinical practice. 
Therefore, neither group is labeled as “intervention” or “control.” 
Please reference Table 1 above for an overall visual explanation of study procedures. The study 
procedures will be discussed in detail in section 4. 
3.1.1 Screening- Baseline 
Potential subjects will be screened using the protocol inclusion and exclusion criteria. 
Parental/guardian permission (informed consent), will be obtained prior to any study related 
procedures being performed. Randomization occurs when infants have been extubated.  However, 
parents of infants who are on higher levels of support, may be approached to introduce the study. 
Consent will be obtained at time of extubation. Once the infant meets all eligibility criteria (, the 

 
 
 
 
 
 
 
5 
subject will be randomized to higher or lower oxygen saturation (SpO2) target ranges and study 
monitoring (3.1.2) will begin.   
3.1.2 Phase 1 – Inpatient monitoring 
After randomization, the alarm settings on the standard hospital equipment will be adjusted 
according to the participant’s group assignment. The study SpO2 ranges are similar to the standard 
of care ranges in the CHOP NICU, where the clinical alarms for infants born <30 weeks are 95% 
(high) and 87% (low) until 36 weeks PMA. After 36 weeks PMA, alarms are set at 98% (high) 
and 90% (low). Participants will continue on the study-- mandated alarm settings until discharge to 
home.  
In addition, participants will be placed on the study monitor in order to facilitate collection of study 
data.  This is similar to the approach previously used in the CHOP and HUP NICUs for the 
Canadian Oxygen Trial.  Nurses will be instructed to follow alarms from the clinical monitors, not 
the study monitor, while the infant is in the NICU.  Per standard of care, the infant will be on the 
clinical monitor continuously.  Every effort will be made to also keep the infant on the study 
monitor continuously; however, it is sufficient to have minimum of 4 days per week/8 hours per day 
of data.  This is consistent with the minimum planned data collection planned for the outpatient 
phase of the study. 
If patients are reintubated, oxygen saturation targets will be at the discretion of the clinical team.  
However, they will be encouraged to maintain the study mandated targets. 
3.1.3 Phase 2 – Outpatient monitoring  
At the time of hospital discharge, as detailed below, families will be given a Masimo oximeter 
along with a device that will transmit the oximetry data back to the study team at CHOP.  They will 
be instructed how to use the device nightly while the child is sleeping at home. 
Infants who are discharged per clinical recommendations on supplemental oxygen will have 
frequent visits in the CHOP Pulmonary Clinic. Oxygen titration and weaning will be standardized 
according to the algorithm in Table 2, below.   
 
Table 2: Home Nasal Cannula Flow Titration Algorithm* 
 
HIGHER SpO2 TARGET 
ARM (>96%) 
LOWER SpO2 
TARGET ARM (>90%) 
Criteria for INCREASING O2 flow rate 
SpO2 < 96% for > 10% of 
recorded time 
SpO2 < 90% for > 10% of recorded time 
Criteria for MAINTAINING current O2 flow 
rate 
SpO2 >= 96% for 90---95% 
of recorded time 
SpO2 > 90% for >= 90% of recorded time but 
NOT > 94% for >= 90% of recorded time 
Criteria for WEANING O2 flow rate 
SpO2 >= 96% for 
>95% of recorded time 
SpO2 > 94% for 
>= 90% of recorded time 
*Decisions will be made by assessment of recorded oximetry. A minimum of 4 days of data, with a minimum of 8 hours per day, will 
be required for analysis to make a wean. Oxygen flow rates will be decreased stepwise: 2 LPM – 1.5 LPM – 1 LPM – 1/2 LPM – 1/4 
LPM – 1/8 LPM. Once the child is stable on 1/8 LPM, he/she will be weaned off for increasing duration of time: first 6 hours, then 12 
hours per day, and finally off completely. 

 
 
 
 
 
 
 
6 
Downloaded oximetry data will be reviewed and decisions about weaning will be made each week 
by the study team (including Dr. Howard Panitch from the Division of Pediatric Pulmonology). In 
the home setting, weans may be performed as often as every week. If an infant loses >5% of body 
weight in any month, no oxygen weans will be made until the weight is regained. If an infant is 
discharged without oxygen or weans off but then meets the criteria for increasing flow on two 
subsequent recordings, the family will be instructed to attend pulmonary clinic for assessment and 
then home oxygen therapy will be instituted. 
3.1.4 Phase 3 – 3 and 6 month corrected age outcomes assessment 
Per standard of care, participants will be evaluated in the CHOP Neonatal Follow-up Program at 3 
and 6 months corrected ages. Several study outcomes, clinical outcomes in particular, will be 
assessed during these clinical visits. Based on the limited existing literature, average age of weaning 
from supplemental oxygen in infants with BPD is between 2-4.5 months corrected age.(9,10)  For 
the current study, the oxygen titration protocol and study oximetry will continue until 6 months 
corrected age, with the expectation that nearly all participants will have weaned to room air by the 
end of the study period. If participants remain on oxygen after the conclusion of the study, the 
pediatric pulmonologist primarily responsible for the child’s ongoing BPD care will make decisions 
about further weaning. For all other participants, ongoing clinical care will be provided by the 
neonatal follow- up clinic and pediatrician. 
3.2 Allocation to Treatment Groups and Blinding 
Infants will be randomized to higher or lower oxygen saturation (SpO2) target ranges. The 
randomization sequence will be determined in advance, stratified by gestational age (<27 and 27-
29 6/7 weeks at birth) and severity of BPD (moderate or severe, see Table 3 below) and balanced 
in random blocks of 2 or 4 patients. Allocation will be concealed in sequentially numbered opaque 
envelopes. The envelope with the lowest number will be opened by study staff. This plan for 
allocation concealment and stratification by key biologic variables will protect the scientific rigor of 
the study. After randomization, study group assignments will not be blinded. Multiples will be 
randomized separately. The two target SpO2 ranges in the current trial represent the middle and 
upper range of the currently accepted range of clinical practice in our center.  
Table 3: Screening Definition of BPD 
Level of respiratory support at 36 weeks PMA 
Eligibility 
Room Air 
Not Eligible (No or Mild BPD) 
<2 L nasal cannula and <30% oxygen* 
Eligible (Moderate BPD) 
<2 L nasal cannula and >=30% oxygen** 
Eligible (Severe BPD) 
>=2 L nasal cannula or any positive pressure 
Eligible (Severe BPD) 
* <30% but receiving supplemental oxygen (22-29%) for at least 12 hours per day 
** >=30% for 12 hours or more per day 
 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to 8 months, not including the screening and consent 
procedures. The baseline phase will last from the time of hospitalization until discharge, the 

 
 
 
 
 
 
 
7 
treatment phase and follow-up phase will take place during the time between discharge and the 6 
month corrected age follow-up appointment. 
 
Many of the children eligible for the study will be followed by the CHOP Chronic Lung Disease 
Program, which has both inpatient and outpatient components. In addition, all children will be 
eligible for routine care in the CHOP Neonatal Follow-up Program (NFP). It is anticipated that most 
outcomes assessments will be performed during routine pulmonary or NFP follow-up appointments. 
Growth parameters between 36 weeks PMA and 40 weeks PMA, 3 months CA, and 6 months CA 
will take place during scheduled follow-up appointments. Questionnaires will be collected at 3 and 
6 months CA. All questionnaires will take approximately 15-30 minutes to complete.    
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
Infants will be recruited from 3 neonatal intensive care units (NICUs):  The Children’s Hospital of 
Philadelphia (CHOP) NICU, the adjacent Hospital of the University of Pennsylvania (HUP) 
NICU, and Pennsylvania Hospital (PAH) NICU.  All outpatient care will take place at CHOP.  
Up to 50 participants may be enrolled to reach our target sample of 42 patients with evaluable 
data. 
3.4 Study Population 
We will enroll male and female infants born less than 30 0/7 weeks at birth of all ethnicities who 
have been diagnosed with moderate or severe Bronchopulmonary Dysplasia; gender and 
race/ethnicity of the sample is expected to mirror the proportions of  the Children’s Hospital of 
Philadelphia, the Hospital of the University of Pennsylvania, and Pennsylvania Hospital patient 
populations. Subjects will be identified through EPIC. Because data about parent quality of life will 
be collected, subjects will be enrolled as parent-child dyads. 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the study. 
3.4.1 Inclusion Criteria 
1) Patient at CHOP,HUP, PAH (including both inborn and outborn infants) 
2) Pre-term males or females infants born at <30 0/7 weeks gestation  
3) Current age 34 0/7 to 43 6/7 weeks postmenstrual age  
4) Diagnosis of moderate or severe Bronchopulmonary Dysplasia (as above)  
5) Infant has never been discharged to home from the hospital 
3.4.2 Exclusion Criteria 
1) Family unlikely to be available for follow-up for 6 months  
2) Congenital anomaly or oncologic process likely to affect growth or respiratory status  
3) Hemoglobinopathy or other blood disorder likely to affect oxygen saturations 
4) Contraindication to nasal cannula use (for example, severe nasal septal breakdown)  

 
 
 
 
 
 
 
8 
5) Pulmonary hypertension requiring pharmacotherapy at the time of screening/enrollment 
6) Intubation at the time of screening/enrollment. (Infants may be approached while requiring 
higher levels of support, but may not enroll until extubation). 
7) Tracheostomy 
8) Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant 
with study schedules or procedures 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of these 
criteria must be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
The Schedule of Study Procedures (Table 1) summarizes the study procedures to be performed at 
each point throughout the study.  Individual study procedures are described in detail below. 
4.1 Inpatient screening and enrollment 
Data elements to be collected are listed in section 5.  
4.2 Inpatient study procedures and data collection 
Details of randomization are provided above in section 3.2.  
4.2.1 Oxygen Saturation Monitoring 
• While inpatient patients will have two monitors, a clinical monitor and a research monitor 
• Alarm limits on the clinical monitor will be changed to reflect randomization assignment. 
• Study oximeter will be placed on baby with the alarms off to ensure consistent data 
collection throughout. 
• Orders in EPIC will be changed to reflect randomization 
 
Data elements to be collected after enrollment and during the inpatient phase are listed in section 5. 
An interpreter will be used to administer questionnaires to non-English speaking subjects.  
4.3 Outpatient study procedures and data collection 
4.3.1 Oxygen Saturation Monitoring 
• Prior to discharge, the family will receive a Masimo oximeter which will transmit data to the 
study team at CHOP.   
• The study team will instruct the family how to use the oximeter correctly. 
• The family will “teach back,” demonstrating that they understand correct use of the monitor. 
• After discharge, the family will attach the probe to the toe and turn on the monitor each 
night while the child is in the crib.  It will be disconnected and turned off in the morning, 
unless the child has been ordered for continuous home pulse oximetry by the discharging 

 
 
 
 
 
 
 
9 
physician.  If clinical orders are for increased monitoring, the clinical orders will be 
followed.   
• Oximetry data will be transmitted to the study team at CHOP nightly between discharge and 
6 months CA.  
• Each week the study team will review a report of the transmitted oximetry data. 
• If the child is discharged on supplemental oxygen (based on clinical judgment), this will be 
weaned based on the child’s assigned target saturation range and the study algorithm. This 
algorithm standardizes the typical approach to weaning used by the CHOP Division of 
Pulmonary Medicine. Downloaded data will be reviewed weekly and decisions about 
weaning will be made by the study team.  In the home setting, weans may be performed as 
often as every week.  If an infant loses >5% of body weight in any month, no oxygen weans 
will be made until the weight is regained.  If an infant is discharged without oxygen or 
weans off but then meets the criteria for increasing flow on two subsequent recordings, the 
family will be instructed to attend pulmonary clinic for assessment and then home oxygen 
therapy will be instituted. 
• Families will be instructed how to evaluate the infant in the case of an alarm, just as with 
home clinical monitoring.  If the infant is kicking/moving and the alarm seems related to 
motion, they will ensure that the probe is well secured and follow for further events.  If the 
alarms are recurrent and the infant has respiratory distress, response will differ based on the 
infant's situation:  If the child is on oxygen, the family will be instructed to turn up the 
oxygen and call the pulmonary team. If the child is not on oxygen and has mild distress or 
cold symptoms, they will be instructed to call the pediatrician.  All children with severe 
respiratory distress and persistent low alarms should go to the emergency room.  This is all 
consistent with the instructions given to all families of children with BPD at the time of 
discharge from the neonatal hospitalization. 
4.3.2 Study outcomes and safety data  
Nearly all participants will have a clinical visit with either the Neonatal Follow-up Program, the 
Chronic Lung Disease Program, or the Pulmonary clinic at about 3 months corrected age.  If none 
of these are scheduled, at visit at the CTRC will be arranged.  If this is not possible, the PI will 
arrange a home visit with the family.  The 3 month assessments can be conducted in any of these 
locations. Specific data elements to be collected during these clinical or study visits are listed in 
section 5. 
4.3.3 End of Study 
Protocol mandated monitoring of oxygen saturations will continue until the child reaches 6 months 
corrected age.  At that time, if the child remains in supplemental oxygen, decisions about 
subsequent monitoring will be made by the child’s pulmonologist.  
If the infant is at home in room air without intermittent hypoxemia (definition below) for 8 
continuous weeks, study monitoring may be discontinued at parental request (earliest possible 
discontinuation of study monitoring at 48 weeks PMA) before 6 months corrected age.  All study 
data will still be collected at 3 and 6 months CA.  

 
 
 
 
 
 
 
10 
4.4 Unscheduled Visits 
It is likely that the participant will have interim clinical visits to the Neonatal Follow-up Program, 
Pulmonary clinic, and the pediatrician.  Wherever possible, study visits will be arranged to align 
with these visits.  
4.5 Concomitant Medication 
The majority of infants at our center are discharged without caffeine therapy; clinicians will be 
encouraged to continue this practice because caffeine is likely to impact incidence of intermittent 
hypoxemia.(8) The study will not dictate diuretic use either in hospital or after discharge, but 
clinicians will be strongly encouraged to wean diuretics before oxygen.(11) Ultimately, however, 
this will be a clinical decision. Exposure to caffeine, diuretics, bronchodilators, steroids, and any 
other medications will be recorded throughout the study. The dates of administration, dosage, and 
reason for use will be included.  
4.6 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They may also 
be discontinued from the study at the discretion of the Investigator for lack of adherence or 
tolerance to testing procedures. Participants will not be withdrawn from the study for missing 
follow up appointments. If the Investigator becomes aware of any serious, related adverse events 
after the subject completes or withdraws from the study, they will be recorded in the source 
documents and on the CRF. 
4.6.1 Early Termination Study Visit 
Subjects who withdraw from the study will be asked to notify the study team of their decision. If 
participants indicate that they do not want us to collect, use, or share their health information any 
longer, we will ask them to inform a research team member or the Principal Investigator, Dr. Sara 
DeMauro. 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review: Screening 
The CHOP/HUP/PAH electronic medical record (EMR) will be accessed to identify potential 
candidates who are CHOP/HUP/PAH patients. Screening for eligibility based on medical record 
review will include: 
• Date of birth (inclusion criterion) 
• Gender 
• Gestational age (inclusion criterion) 
• Race 

 
 
 
 
 
 
 
11 
• Ethnicity 
• Moderate or severe BPD based on the NIH consensus definition at 36 weeks 
postmenstrual age (inclusion criterion)(12) 
• Presence of any exclusion criteria 
5.1.2 Inpatient Data Collection 
After enrollment and randomization, the following data will be collected from the EMR while the 
patient is in the hospital: 
• Birthweight 
• Birth hospital 
• Date of transfer to CHOP,HUP, of PAH (if applicable) 
• Antenatal steroid treatment 
• Reason for preterm birth 
• Respiratory support  
• Growth parameters at 36 weeks PMA 
• Growth parameters at 40 weeks PMA 
• Treatment with the following medications for BPD: iNO, postnatal steroids, inhaled 
bronchodilators, inhaled steroids, other 
• Any surgeries 
• Neonatal morbidities (surgical NEC, PDA ligation, ROP surgery, etc). 
• Screening for pulmonary hypertension 
5.1.3 Discharge Data Collection 
• Discharge feeding plan 
• Discharge respiratory support 
• Discharge medications 
• Discharge growth parameters 
• Discharge date 

 
 
 
 
 
 
 
12 
5.1.4 Outpatient Data Collection 
During the remainder of the study period, the following data will be collected: 
• Rehospitalizations: location, duration, and ICU care, primary reason for hospitalization 
• Medication use 
• Visits to doctor or emergency room, with reason 
• Procedures or surgeries 
• Growth parameters as assessed at any clinical visit(s) 
• Mode of feeding 
• Developmental assessment (Bayley screener)  
5.1.5 Parental Data Collection 
• Infant quality of life questionnaires 
5.2 Efficacy Evaluations 
5.2.1 Efficacy Evaluations: Oximetry 
This pilot trial is designed to assess the efficacy of continuous transmission of pulse oximetry from 
the home environment, for use in oxygen titration and monitoring for clinical care and research 
purposes.  Therefore the study outcomes are designed to assess the efficacy of the study monitoring 
itself as well as the intervention of randomization to higher or lower oxygen saturation target ranges 
for infants with BPD.   
For this study, we define intermittent hypoxemia as SpO2<80% for >30 seconds.  In keeping with 
the prior literature, we will also report severe IH events, defined as SpO2<80% for >60 seconds.  In 
the current study, we will utilize 2-second sampling and averaging times.  IH will be measured 
longitudinally throughout the study period in all participants regardless of home oxygen use.  IH 
will be reported as weekly average number of events per “night” based on 8 hours of recorded 
oximetry data per night.  If data are not available for all nights in a week, the available data will be 
used to estimate average number of events per night for that week.  Specific outcomes of interest 
are differences between the two groups in incidence of IH at 40 weeks PMA, 3 months CA, and 6 
months CA.  In addition, we will report percent of recording time spent <80%, <85% and <90% 
SpO2 over the study period.  
Duration of exposure to supplemental oxygen will be measured as the number of weeks between 36 
weeks PMA (the time of formal diagnosis of BPD) and complete discontinuation of supplemental 
oxygen. This outcome is defined in weeks, not days, because this more closely matches the pace 

 
 
 
 
 
 
 
13 
with which changes are made in the outpatient setting. Prior studies demonstrated that it can be 
challenging, but nevertheless possible to keep infants in goal SpO2 ranges during hospitalization. 
However, no studies have performed this maneuver after discharge.  To demonstrate successful 
implementation of our study intervention and monitoring technology, percent of usable data and 
percent of time with SpO2 in target range over time will be reported.  Time with SpO2 in the target 
range will be reported as a percent of oximeter recordings with SpO2 in range, out of total recorded 
time.  These outcomes are key components of demonstrating feasibility of the study intervention for 
future research and clinical use.   
5.2.2 Efficacy Evaluations: Clinical 
In this pilot study, physiologic (oximetry) data are the primary outcomes.  All clinical 
outcomes/assessments of efficacy are exploratory and descriptive. Methods and timing of measures 
that will be used to assess efficacy are: 
Primary Clinical Outcome: 
Growth in kilograms between 36 weeks PMA and 6 months CA as well as other growth 
parameters. 
• Change in Length (cm) 
• Weight for length 
• Head circumference (cm) 
Secondary Clinical Outcomes: 
• Feeding questionnaire: The questions that will be asked at 3 and 6 months are selected 
assess feeding skills and estimate caloric intake.  The questions are selected from longer 
questionnaires administered as part of the Millennium Birth Study, with permission from the 
author of the original study.(13)  
• The ITQOL---SF47- Parent and child quality of life survey: The Infant Toddler Quality of 
Life Questionnaire™ (ITQOL) was developed for use in infants and toddlers at least 2 
months of age up to 5 years. The Infant Toddler Quality of Life Questionnaire™ (ITQOL) 
adopts the World Health Organization's definition of health, as a state of complete physical, 
mental and social wellbeing and not merely the absence of disease. The survey was 
developed following a thorough review of the infant health literature and a review of 
developmental guidelines used by pediatricians. The ITQOL includes questions that assess 
the impact of health on both child and parent quality of life. 
• Medical resource utilization recorded at 3 and 6 months corrected age: medications 
(including dose, route, frequency, and indication), doctor and emergency room visits, 
hospitalizations (whether or not in ICU, duration, and indication), therapies (type and 
frequency), and home equipment use.  These data will be extracted from the EMR wherever 
possible and verified with the participant’s parent(s). 
• Development: Per standard of clinical care, the Bayley Scales of Infant Development- 3rd 
Edition Screening Test is administered to all children who attend the Neonatal Follow-up 
Program (NFP) at 6 months corrected age.  (All children eligible for this study will be 

 
 
 
 
 
 
 
14 
followed at the NFP per standard of care) Results of this clinical evaluation will be recorded 
for the study. 
5.3 Safety Evaluation 
Subject safety will be monitored by adverse events, as well as the clinical outcomes as described 
above.  Potential adverse clinical outcomes based on the prior literature are pneumonia/BPD 
exacerbations and detrimental effects on parental quality of life.   
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoints are the incidence of intermittent hypoxemia (IH, SpO2 <80% for >=30 
seconds) and total duration of hypoxia up to 6 months corrected age among infants with BPD 
randomized to higher versus lower SpO2 target ranges. 
6.2 Secondary Endpoints 
All secondary endpoints in this pilot study are essentially exploratory and descriptive.  The primary 
clinical outcome is growth in kilograms between 36 weeks PMA and 6 months CA.  In addition, the 
study will also report: 
• The change in other growth parameters - length (cm), weight for length, and head circumference 
(cm) - between 36 weeks PMA and 40 weeks PMA, 3 months CA, and 6 months CA. 
• Differences between groups on a standardized feeding questionnaire at 3 and 6 months CA. 
• Differences between groups in parent and child quality of life at 3 and 6 months CA. 
• Differences between the groups in health care utilization at 3 and 6 months CA. 
• Differences between the groups in development at 6 months CA.  
• Safety, assessed as differences in growth, re-hospitalizations, and any safety events at 3 and 6 
months CA. 
6.3 Statistical Methods 
6.3.1 Baseline Data  
Standard descriptive statistics will be used to compare baseline characteristics of the two groups, 
which may be different despite randomization in this small pilot study. 
6.3.2 Efficacy Analysis 
The primary analysis will be based on an intention to treat approach and will include all randomized 
subjects. Interpretation and analysis of downloaded saturation data throughout the study will be 
managed in two ways. Saturation data will be cleaned, processed, and analyzed weekly.  This will 
allow real-time assessments in order to ensure that the oximeter is being applied routinely and 
sufficient usable data are available.  In addition, the data will be analyzed to determine whether the 
participant is having SpO2 below the target range that would necessitate either increase in flow or 
medical attention.   

 
 
 
 
 
 
 
15 
Generalized estimating equations will be used for continuous primary outcomes such as frequency 
of IH and growth and logistic models for binary outcomes. Models will be adjusted for potential 
confounders that are significantly different in bivariate testing, because differences may exist 
despite randomization due to small sample size. Variables that will be considered for inclusion in 
the model are gender, gestational age, birth weight, race, small size for gestational age, and severity 
of BPD. The remaining exploratory outcomes will be compared between groups with simple 
bivariate tests such as t-tests and x2 tests.  Exploratory subgroup analyses will be performed to 
evaluate the effect of the intervention on the gestational age and severity of BPD strata. Lastly, we 
will test for PMA week-specific differences between study groups through regression models 
controlling for key covariates, and using adjustments to account for multiple testing across PMA 
weeks. Given the sample size of this pilot study, we will likely not have sufficient power to draw 
definitive conclusions in these exploratory analyses; however, these approaches to the data are 
likely to be valuable in planning future studies.   
6.3.3 Safety Analysis 
All subjects entered into the study will be included in the safety analysis. The frequencies of AEs by 
type, body system, severity and relationship to study arm will be summarized. SAEs (if any) will be 
described in detail. 
6.4 Sample Size and Power 
No preliminary data about incidence of IH in infants with moderate or severe BPD are available. 
Therefore, our sample size is based on extrapolations from the existing studies.  Rhein reported 8.2 
+/- 11.5 events of 5 seconds or longer per hour (197 per day) at 36 weeks PMA.(8)  Poets reported a 
median 88.4 events of 10 seconds or longer per day in the Canadian Oxygen Trial.(7) We assume 
that fewer than half of these will be longer events that meet our study definition of IH, and estimate 
that our study participants will have between 20--30 IH events per 8-hour period at baseline.  We 
plan to recruit 42 participants with useable data, which will provide sufficient power to detect a 
relative reduction of 30% between the high and low SpO2 target groups if the baseline rate is 30 
events per 8 hours. Therefore, our target sample size is 42 children with complete data. 
Mean weight at 36 weeks PMA based on the Olsen growth curves is 2.8 kg,(14) and mean weight at 
6 months CA based on the WHO growth curves is 7.9 kg.(15) Therefore, we assume a mean growth 
of 5.1 kg in the higher SpO2 group and less weight gain in the lower SpO2 group. The target sample 
size of 42 children will provide >80% power to detect a mean difference in growth of 0.5kg 
between the two study groups.  
6.5 Interim Analysis 
Interim analyses will be performed after 10 and 20 participants complete the study observation 
period (25% and 50%).  The goal of the two interim analyses is to evaluate rates of drop-out, ensure 
that sufficient useable data are acquired, assess mean rates of IH across the entire population, and 
review accumulating safety data. 
 

 
 
 
 
 
 
 
16 
7 
STUDY INTERVENTION  
7.1 Description 
We will randomize infants with moderate or severe BPD to lower (target SpO2 of 90-94%) or 
higher SpO2 target ranges (target SpO2 of >=96%). The study team will then use novel 
technology to monitor infants starting at randomization, continuing after discharge and until 6 
months corrected age, titrating supplemental oxygen to achieve these target SpO2 ranges. 
All trial participants will be provided with a study oximeter. Families will be instructed to use 
the study monitor continuously each night or when the baby is napping. The research monitor 
will stay in the child’s sleep space and set with alarm limits of 79% and 101% and will be 
attached nightly when the infant is placed in the bed (in addition to the clinical monitor if 
prescribed). The research oximeter will be set for 2 second averaging and sampling. In addition, 
we will collect photoplethsymgraphy (PPG) data at a rate not greater than 100 Hz to aid in 
identifying errors in the SpO2, likely caused by motion artifact. 
Infants enrolled in the current study who are discharged on home oxygen will be provided with 
standard clinical monitors by their home care companies, which will be set with alarm limits of 
88% and 101%, and used with a frequency determined by the discharging clinician.  
7.1.1 Treatment Compliance and Adherence 
Data will be transmitted continuously from the home oximeter to the study team at CHOP.  Data 
will then be reviewed weekly to ensure that families are using the device nightly as required per 
protocol, as well as to evaluate the integrity of transmitted data.  If families are not using the 
monitor, the study team will contact them to facilitate adherence to the study protocol. 
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
8.2 Adverse Event Reporting 
The Investigator is responsible for recording and reporting unanticipated problems related to 
research that occur during and after study treatment. Unanticipated problems related to the research 
involving risks to subjects or others that occur during the course of this study (including SAEs) will 
be reported to the IRB in accordance with CHOP IRB SOP 408: Unanticipated Problems Involving 
Risks to Subjects. AEs that are not serious but that are notable and could involve risks to subjects 
will be summarized in narrative or other format and submitted to the IRB at the time of continuing 
review.  
8.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an intervention 
(drug, biologic, or other intervention).  The occurrence does not necessarily have to have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable or unintended sign 

 
 
 
 
 
 
 
17 
(including an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report form with 
a full description including the nature, date and time of onset, determination of non-serious versus 
serious, intensity (mild, moderate, severe), duration, causality, and outcome of the event. 
8.4 Definition of a Serious Adverse Event (SAE) 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major event of its 
type.  A severe AE does not necessarily need to be considered serious.  For example, nausea which 
persists for several hours may be considered severe nausea, but would not be an SAE.  On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild stroke, but 
would be an SAE 
8.4.1 Relationship of SAE to intervention 
The relationship of each SAE to the study intervention should be characterized using one of the 
following terms in accordance with CHOP IRB Guidelines: definitely, probably, possibly, unlikely 
or unrelated.  
8.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be filed 
using the eIRB system and in accordance with the timeline below. External SAEs that are both 
unexpected and related to the study intervention will be reported promptly after the investigator 
receives the report.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time of 
continuing review 

 
 
 
 
 
 
 
18 
8.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes 
the investigator’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) should be submitted to the 
IRB. The investigator is responsible for ensuring that all SAE are followed until either resolved or 
stable.  
8.6 Medical Emergencies 
It is possible that a home monitor will alarm repeatedly for low saturations.  In this case, the family 
will be instructed to contact the child’s doctor and if necessary bring the child to the emergency 
room.  Such events will be monitored closely and reported to the IRB as necessary according to the 
above guidelines about adverse event reporting.  
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
The plan for randomization is described above in section 3.2. 
9.1.2 Blinding 
The plan for allocation concealment is described above in section 3.2.  Given the nature of the 
intervention to be evaluated participants and research staff will not be blinded to group assignment.  
9.2 Data Collection and Management 
The proposed research will be carried out using, in part, computing facilities available at the 
PRECISE (Penn Research in Embedded Computing and Integrated Systems Engineering) Center at 
the University of Pennsylvania. The PRECISE center has a large dedicated facility for embedded 
system development and prototyping with an array of electronic measurement and instrumentation 
equipment.  
The oximeters each have a port into which a small computer/dongle designed for this study is 
plugged.  The dongle contains a wi-fi device (“hot spots") that will transmit the data 
continuously.  The dongle can store data in the case of dropped wi-fi signal. We will transmit SpO2 
data and pulse rate, along with some data that indicate the quality of the signal, but not the 
waveforms. Only oximeters on loan from Masimo will be used for this study. In addition only 
cellular modems provided by CHOP will be used for this study.  
The lab provides secure storage in addition to the hardware and computing resources necessary to 
maintain a large--‐scale monitoring system. The PRECISE center has developed the device that will 
transmit data from the Masimo monitor to the study team at CHOP wirelessly.  They will maintain 
these devices and the data transmission throughout the study.  This team will not have access to 
patient identifiers; data streams will be labeled only with study ID numbers.  However, the data 
streams will be date and time stamped, which is essential in order to ensure data integrity. PRECISE 
will then strip dates and may perform analyses on de-identified and coded data set with dates 

 
 
 
 
 
 
 
19 
removed, therefore they will not be considered engaged in human subject’s research nor is there a 
need for a data sharing agreement. 
As mentioned, data may be managed and stored in a password-protected database using the 
research-focused electronic web-based data capture system REDCap (Research Electronic Data 
Capture). REDCap is a secure software solution and workflow methodology for supporting clinical 
research databases developed by the informatics core at Vanderbilt University. Automated time-
stamped backup files are made daily from the replicated database by CHOP Research Information 
Systems. Backup files are encrypted and transferred to the secure CHOP Research Information 
Systems Storage Area Network (SAN) accessible only to designated personnel. REDCap provides 
automated export procedures for seamless data downloads to Excel and commonly-used statistical 
packages. The database will incorporate range and consistency checks to ensure quality control and 
will signal the presence of questionable items. Only study team members will have access to the 
REDCap database for data entry under the supervision of and after training by the PI. Hard copies 
of data instruments will be stored in a locked cabinet in a locked office in the Division of 
Neonatology at CHOP. 
To maintain confidentiality, participants will be assigned a unique identifier that contains no 
protected health information. All source documents will have the study identifier only. Access to 
the identifiers of the coded data will be controlled by the PI and only study team members will have 
access to the electronic and paper data.  
Individuals who withdraw from the study after enrollment will be removed from the main study 
database (s) and placed in to a separate encrypted, password-protected database maintained at 
CHOP. This file will be deleted at the end of the study. Records will be retained in compliance with 
CHOP Policy A-3-9 
9.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy.  Study personnel will not use data and records 
for any purpose other than conducting the study. To maintain confidentiality, informed consent will 
occur privately and all study data will be coded as described above in 9.2 Data Collection and 
Management. 
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and any 
recipient researchers (including others at CHOP) before sharing a limited dataset (PHI limited to 
dates and zip codes).  
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
The PI will be responsible for monitoring the data and safety of all participants. All study 
procedures will receive IRB approval prior to recruitment or enrollment of participants. In addition 
to the data management procedures outlined above, the PI will hold monthly study team meetings to 
evaluate the safety and progress of all research procedures. The PI will also be responsible for 
overseeing training of the research staff in the recruitment of subjects according to the participant 

 
 
 
 
 
 
 
20 
inclusion criteria and maintaining the study protocol set forth in this study.  Standard procedures for 
all data collection methods will be reviewed at the start and periodically throughout the study. Data 
checks for errors will be performed prior to analysis. The PI and research staff will also review 
adverse events and any concerns about participant distress that might not qualify as an adverse 
event. Adverse events and serious adverse events will be reported to the CHOP IRB and other 
regulatory authorities in accordance with federal and other relevant regulations.  
 
In addition, an independent data monitor for the BPD STar study has been identified. This person is 
a biomedical engineer with expertise in streaming oximetry data and clinical studies of newborn 
infants utilizing oximetry.  She will be responsible for participating in assessments of data quality as 
pretain to the oximetry data and analyses. 
 
9.4.2 Risk Assessment 
Confidentiality. Protected health information will be collected as part of study records, and breaches 
of this information outside of the study team resulting in loss of confidentially is a potential risk. 
Every precaution will be taken to secure participants’ personal information to ensure confidentiality. 
Our institution maintains strict policies, systematic procedures and sufficient resources for data 
management in compliance with HIPAA and IRB regulations for safeguarding participant 
information. Electronic data will be stored in secure, password-protected systems. Paper data will 
be stored in a locked cabinet in the locked Neonatology office suite at CHOP. Participants will be 
assigned a unique identifier that contains no protected health information. Access to the identifiers 
of the coded data will be controlled by the PI and only study team members will have access to the 
electronic and paper data. 
 
Saturation Targeting. Targeting high oxygen saturations with supplemental oxygen may be 
associated with increased pulmonary oxygen toxicity, retinopathy of prematurity, decreased quality 
of life, without improving neurologic outcomes.  Targeting lower oxygen saturation ranges with less 
supplemental oxygen may be associated with more episodes of hypoxia which might impact growth 
and development. Subjects will be monitored simultaneously with a clinically indicated pulse 
oximeter monitor. There are subject discontinuation and study stopping criteria as well as 
monitoring procedures in place and, in addition to the PI, an independent monitor will conduct data 
safety monitoring. 
 
Oxygen saturation monitors. Oxygen saturation monitors are routinely used in the NICU and also 
frequently indicated for home use in infants with BPD. Participants will follow routine clinical 
routines for frequent site relocation of the oximeter sensors (probes), which will eliminate the risk 
of any significant skin irritation. The monitor will have an alarm, which will sound if the sensor is 
not working or if the infant’s oxygen level is too low, which may be bothersome to families. 
Questionnaires. Risks are not greater than minimal. Completing questionnaires in regards to health 
behavior activities could potentially be distressing for some parents/caretakers, however it is not 
likely that these activities will create additional distress beyond that which is already present. 
9.4.3 Potential Benefits of Trial Participation 
Direct benefits are that participants may have improved symptoms and/or disease management or 
improved growth and development and decreased cost. It is possible that infants with BPD, 

 
 
 
 
 
 
 
21 
who are at high risk for adverse outcomes, might benefit from targeted management of oxygen 
saturations over the first few months of life. 
Indirect study benefits include benefitting infants with BPD in the future by increasing our 
understanding of effective oxygen saturation targets. This study will yield important knowledge 
about the post--‐discharge care of infants with BPD. 
9.4.4 Risk-Benefit Assessment 
The potential benefits of participation exceed any minimal risks. 
9.5 Recruitment Strategy 
Research will take place at The Children’s Hospital of Philadelphia (CHOP), Hospital of the 
University of Pennsylvania (HUP), and Pennsylvania Hospital (PAH). Infants will be recruited from 
the neonatal intensive care unit (NICU) at the Children’s Hospital of Philadelphia, which is a 97-
bed quaternary referral center, and the adjacent Hospital of the University of Pennsylvania NICU, 
which is a 36-bed tertiary inborn unit. In addition, Infants will be recruited from Pennsylvania 
Hospital, Which is a 50- bed tertiary inborn unit. The research coordinator or PI will approach 
families of eligible infants for consent while the infant is still hospitalized in the CHOP, HUP, 
or PAH NICU and has reached at least 34 weeks corrected age. Adequate time to review the 
consent, consider risks and benefits of participation, and ask questions will be provided. Signed 
informed consent will be obtained from a parent before a child is enrolled and randomized. 
9.6 Informed Consent/Assent and HIPAA Authorization 
Potential study candidates will be screened for eligibility based on the inclusion and exclusion 
criteria. Parent or legal representative of each potential participant will receive a verbal and written 
explanation of the purposes, procedures and risks of the study. Families will have time to consider 
participation and make a decision at a later time. A study physician will be available to explain the 
medical aspects of the study and answer questions during the consent process. Informed consent 
procedures will occur in the participant’s room or remotely. A combined informed consent-HIPAA 
authorization document will be used. Parents will have the opportunity to ask questions. The parent 
or legal representative must provide written informed consent prior to the start of any study 
activities. Consent will be documented and a copy of consent documents will be provided to the 
parent or caregiver. Decision not to participate in this study will not affect access to or quality of 
clinical services. 
Due to Covid-19 and with reduced access to the workplace and social distancing that is enforced, 
we will provide the option to consent parents and enroll subjects remotely in one of two ways – 
1) The REDCAP survey method with an eConsent that will be emailed to the parents with telephone 
and/or video-conferencing to follow, if feasible, to answer questions, and a signed copy returned 
automatically if they agree, or 
2) By making a paper copy of the consent available to the parents ahead of time with either the 
research team mailing, emailing or faxing the consent or the research team or clinical staff 
providing a paper copy, followed by either telephone and/or video-conferencing or face-to-face to 
address their questions or concerns. 

 
 
 
 
 
 
 
22 
A valid electronic signature will be obtained via RedCap that the signature is logically associated 
with the individual. The consent form/HIPAA authorization will include instructions to print or save 
a copy of the page(s) presented on the electronic device. The subject will be able to print (or save) a 
copy of the consent form (with or without signature). Alternatively, the form could be emailed to 
the subject. 
Regardless, the method by which consent is obtained, a study physician will be available to explain 
the medical aspects of the study, risks and benefits of the study, and answer questions during the 
consent process. 
A short form will be available and translated into the subjects preferred language during the consent 
process for participants with limited English proficiency. The short form consent process will not 
occur remotely or via electronic form. Potential participant will receive a verbal and written 
explanation of the purposes, procedures and risks of the study.  A translator will be available either 
in person or over the phone whenever needed. The study summary document and short form 
consent form (signed by the interpreter) will be obtained in person or via fax, scan or email. 
9.6.1 Waiver of Assent 
A waiver of child assent is requested due to the age of the children participating in the study.  
9.7 Payment to Subjects/Families 
Participants will be compensated up to a total of $300 ($50 per month, up to 6 months CA), through 
a ClinCard (loadable debit card) for their time and inconvenience, given that the study monitor must 
be used nightly and the family will have at least weekly interaction with the study team. Participants 
will also receive a BPD Star Tote at discharge to aid in convenient transportation of the study 
equipment.  
 
10 PUBLICATION 
Study findings will be disseminated in peer-reviewed scientific publications and at scientific 
meetings. The CHOP investigators will have access to complete trial data. Published data will be 
deidentified. 
 
 
 
 
 
 

 
 
 
 
 
 
 
23 
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