Impact of Continuous Positive Airway Pressure Level on Ventilation/Perfusion Mismatch in Premature Infants: a Phase II Clinical Trial
Phase: NA
Conditions: Infant, Premature, Diseases, Respiratory Insufficiency Syndrome of Newborn
Sponsor: Children's Hospital of Philadelphia

Title: Impact of CPAP Level of V/Q Mismatch in Premature Infants  
NCT02983825 
Last Protocol Approval Date: 2/20/19  
 

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Modiﬁcation
Basic Info
Conﬁrmation Number:
chjddjdg
Protocol Number:
825874
Created By:
BAMAT, NICOLAS
Principal Investigator:
BAMAT, NICOLAS
Protocol Title:
Impact of continuous positive airway pressure (CPAP) level on ventilation/perfusion mismatch in premature infa
phase II clinical trial.
Short Title:
CPAP and V/Q in premature infants
Protocol Description:
Purpose: To measure the responsiveness of ventilation/perfusion (V/Q) mismatch to a strategy of 
individualized CPAP level selection. Population: Up to 30 infants of corrected gestational age 
27-35 weeks, chronologic age greater than 24h, requiring oxygen supplemental oxygen while on 
CPAP. Approach: single-arm prospective phase-II clinical trial with application of a protocol of 
step-wise changes in CPAP level guided by improvements in V/Q mismatch, measured using a 
non-invasive technique.
Submission Type:
Biomedical Research
Application Type:
FULL
PennERA Protocol Status
Approved
Resubmission*
No
Are you submitting a Modiﬁcation to this protocol?*
Yes
Current Status of Study
Study Status
Currently in Progress
If study is currently in progress, please enter the following
Number of subjects enrolled at Penn since the study was initiated
12
Actual enrollment at participating centers
15
If study is closed to further enrollment, please enter the following
Number of subjects in therapy or intervention
0

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Number of subjects in long-term follow-up only
0
IRB Determination
If the change represents more than minimal risk to subjects, it must be reviewed and approved by the 
IRB at a convened meeting. For a modiﬁcation to be considered more than minimal risk, the proposed 
change would increase the risk of discomfort or decrease beneﬁt. The IRB must review and approve the 
proposed change at a convened meeting before the change can be implemented unless the change is 
necessary to eliminate an immediate hazard to the research participants. In the case of a change 
implemented to eliminate an immediate hazard to participants, the IRB will review the change to 
determine that it is consistent with ensuring the participant&prime;s continued welfare. Examples: 
Convened Board Increase in target enrollment for investigator initiated research or potential Phase I 
research Expanding inclusion or removing exclusion criteria where the new population may be at 
increased risk Revised risk information with active participants Minor risk revisions that may affect a 
subject&prime;s willingness to continue to participate Expedited Review Increase in target enrollment 
at Penn where overall enrollment target is not exceeded or potentially sponsored research Expanding 
inclusion or removing exclusion where the new population has the same expected risk as the previous, 
based on similarities of condition Revised risk information with subjects in long-term follow-up Minor 
risk revisions with no subjects enrolled to date 
Expedited Review
Modiﬁcation Summary
Please describe any required modiﬁcation to the protocol. If you are using this form to submit an 
exception or report a deviation, enter 'N/A' in the box below.
Increase in total enrollment in order to apply the study intervention in 20 subjects. To date, 4 subjects 
have enrolled (deﬁned by provision of informed consent) who subsequently became ineligible and 
could not undergo the intervention. We will increase total enrollment to 30 subjects, in order to allow 
for these subjects who enroll but become ineligible after consent, but will consider accrual complete 
when 20 subjects undergo the study intervention.
Risk / Beneﬁt
Does this amendment alter the Risk/Beneﬁt proﬁle of the study?
No
Change in Consent
Has there been a change in the consent documents?
No
If YES, please choose from the options below regarding re-consenting
Deviations
Are you reporting a deviation to this protocol?*
No
Exceptions
Are you reporting an exception to this protocol?*
No

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Protocol Details
Resubmission*
Yes
Study Personnel
Principal Investigator
Name:
BAMAT, NICOLAS
Dept / School / Div:
4392 - PE-Pediatrics
Campus Address
Mail Code
4399
Address:
CHOP 
3400 CIVIC CENTER BLV
City State Zip:
PHILADELPHIA PA 19104-4399
Phone:
-
Fax:
-
Pager:
Email:
bamatn@email.chop.edu
HS Training Completed:
Yes
Training Expiration Date:
09/07/2017
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Study Contacts
Name:
MCANLIS, CAROLYN
Dept / School / Div:
2100 - Health System
Campus Address
Mail Code
Address:
Contracted Emp Non-UPHS Paid
Neonatology Services
City State Zip:
Phone:
Fax:
Pager:
Email:
mcanlisc@email.chop.edu
HS Training Completed:
Yes
Training Expiration Date:
03/02/2018
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA

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Name:
ABBASI, SORAYA
Dept / School / Div:
4392 - PE-Pediatrics
Campus Address
Mail Code
4399
Address:
CHOP newborn care at Pennsylva
800 SPRUCE ST 
City State Zip:
PHILA PA 19107-0000
Phone:
215-977-9779
Fax:
-
Pager:
Email:
abbasis@uphs.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
04/05/2018
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Name:
WOODFORD, EMILY
Dept / School / Div:
2100 - Health System
Campus Address
Mail Code
Address:
Contracted Emp Non-UPHS Paid
CHOP Neonatology
City State Zip:
Phone:
-
Fax:
-
Pager:
Email:
Emily.Woodford@pennmedicine.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
09/24/2021
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Other Investigator
None
Responsible Org (Department/School/Division):
4392 - PE-Pediatrics
Key Study Personnel
Name:
MANCINI, TONI
Department/School/Division:
Health System
HS Training Completed:
Yes
Training Expiration Date:
02/15/2021
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA

Page 5 of 20
Name:
HANDLEY, SARA
Department/School/Division:
PE-Pediatrics
HS Training Completed:
Yes
Training Expiration Date:
08/07/2018
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Name:
CHAUDHARY, AASMA
Department/School/Division:
Health System
HS Training Completed:
Yes
Training Expiration Date:
10/25/2019
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Disclosure of Signiﬁcant Financial Interests*
Does any person who is responsible for the design, conduct, or reporting of this research protocol have 
a FINANCIAL INTEREST?
No
Penn Intellectual Property*
To the best of the Principal Investigator's knowledge, does this protocol involve the testing, 
development or evaluation of a drug, device, product, or other type of intellectual property (IP) that is 
owned by or assigned to the University of Pennsylvania?
No
Certiﬁcation
I have reviewed the Financial Disclosure and Presumptively Prohibited Conﬂicts for Faculty 
Participating in Clinical Trials and the Financial Disclosure Policy for Research and Sponsored 
Projects  with all persons who are responsible for the design, conduct, or reporting of this research; and 
all required Disclosures have been attached to this application.
Yes
Biomedical Research
Clinical Trial*
Is this a clinical trial?
Yes
If Yes, please be aware that for each clinical trial conducted or supported by a Federal department or 
agency, one IRB-approved informed consent form used to enroll subjects must be posted by the 
awardee or the Federal department or agency component conducting the trial on a publicly available 
Federal Web site that will be established as a repository for such informed consent forms.
Investigator Initiated Trial*
Is this an investigator initiated trial?
No
Drugs or Devices*
Does this research study involve Drugs or Devices?
No
IND Exemption
For studies that fall under an IND exemption, please provide the number below

Page 6 of 20
For studies including IND or IDE's, please provide the number(s) below
IDE Review*
NOTE: For research involving investigational devices, you are required to review the guidance on 
Managing Research Device Inventory. Consult the Penn Manual for Clinical Research: https://
www.med.upenn.edu/pennmanual/secure/investigational-product-management-at-sites-not-using-
investigational-drug-services-(ids).html Please check the box Yes if you have reviewed the guidance.
Yes
Research Device Management*
Please indicate how research device(s) will be managed.
Not Applicable (no investigational devices)
Drug, Herbal Product or Other Chemical Element Management *
Please indicate how drugs, herbal products or other chemical entities will be managed.
Not Applicable (no drugs, herbal products or other chemical entities)
Radiation Exposure*
Are research subjects receiving any radiation exposure (e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, 
FDG, Tc-99m, etc.) that they would not receive if they were not enrolled in this protocol?
No
Gene Transfer*
Does this research involve gene transfer (including all vectors) to human subjects?
No
Human Source Material*
Does this research include collection or use of human source material (i.e., human blood, blood 
products, tissues or body ﬂuids)?
No
CACTIS and CT Studies*
Does the research involve Center for Advanced Computed Tomography Imaging Services (CACTIS) 
and CT studies that research subjects would not receive if they were not part of this protocol?
No
CAMRIS and MRI Studies*
Does the research involve Center for Advanced Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) and MRI studies that research subjects would not receive if they were not part of this 
protocol?
No
Investigational Agent or Device within the Operating Room*
Does the research project involve the use of an investigational agent or device within the Operating 
Room?
No
Cancer Related research not being conducted by an NCI cooperative group*
Does this protocol involve cancer-related studies in any of the following categories?
No
Processing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
In-House Manufacturing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
Medical Information Disclosure*
Does the research proposal involve the use and disclosure of research subject's medical information for 
research purposes?

Page 7 of 20
Yes
If the answer is YES, indicate which items is is provided with this submission:
Modiﬁed research informed consent document that incorporates HIPAA requirements
CTRC Resources*
Does the research involve CTRC resources?
No
Pathology and Laboratory Medicine Resources*
Will samples be collected by hospital phlebotomy and/or processed or analyzed by any of the clinical 
laboratories of the University of Pennsylvania Health System?
No
Research Involves Apheresis, Cell Collection, and/or Blood Product Collection*
Does this research involve collection of blood products in the Penn Donor Center and/or the use of 
apheresis for treatment or collection of cells or other blood components?
No
Research involving blood transfusion or drug infusions*
Will your research involve blood transfusion or infusion of study drug in 3 Ravdin Apheresis Unit for 
research purposes?
No
Trial in Radiation Oncology
Is this research a prospective trial being done in Radiation Oncology, and if so, has this protocol been 
approved by the Radiation Oncology Protocol committee?
N/A
Study in Radiation Oncology
Is this research a retrospective study being done in Radiation Oncology, and if so, has this project been 
reviewed by the Radiation Oncology Clinical Research Group?
N/A
Use of UPHS services*
Does your study require the use of University of Pennsylvania Health System (UPHS) services, tests or 
procedures*, whether considered routine care or strictly for research purposes?
No
Primary Focus*
Clinical Trial (prospectively assigning subjects to health-related interventions to evaluate outcomes)
Protocol Interventions
Sociobehavioral (i.e. cognitive or behavioral therapy)
Drug
Device - therapeutic
Device - diagnostic (assessing a device for sensitivity or speciﬁcity in disease diagnosis)
Surgical
x Diagnostic test/procedure (research-related diagnostic test or procedure)
Obtaining human tissue for basic research or biospecimen bank
Survey instrument
None of the above
The following documents are currently attached to this item:
There are no documents attached for this item.

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Department budget code
None
Multi-Site Research
Other Sites
Site:
The Children's Hospital of Philadelphia
Contact:
Pi:
Nicolas Bamat
Mail:
3401 Civic Center Blvd
Philadelphia, PA 19104
Phone:
215-300-1356
Email:
bamatn@email.chop.edu
Site:
Pennsylvania Hospital
Contact:
Pi:
Nicolas Bamat
Mail:
800 Spruce St
Philadelphia, PA 19107
Phone:
Email:
Management of Information for Multi-Center Research
The following documents are currently attached to this item:
There are no documents attached for this item.
Protocol
Abstract
Background: Infants born prematurely are at high risk of developing bronchopulmonary dysplasia 
(BPD). BPD is associated with death as well as long-term respiratory and neurodevelopmental 
impairments in childhood survivors. Very few evidence-based therapies for preventing BPD exist. Of 
these, the preferential use of nasal continuous positive airway pressure (CPAP) over mechanical 
ventilation (MV) is the most novel. CPAP applies a continuous distending airway pressure to lungs 
prone to collapse, while avoiding the ventilator-induced lung injury of MV known to contribute to the 
development of BPD. Sometimes, two levels of alternating pressure are applied, with higher and lower 
pressure levels alternating. This is called bi-level non-invasive support. When there is only one pressure 
level, this is the CPAP level. In bi-level support, the lower pressure level is considered the CPAP level. 
By promoting open lungs, CPAP helps prevent atelectasis. This improves oxygenation, in large part by 
reducing ventilation/perfusion (V/Q) mismatch. However, the overall beneﬁt of preferential CPAP over 
MV is modest. An explanation for this limited beneﬁt may be that most infants at highest risk for BPD 
fail CPAP and are nonetheless exposed to MV and its associated harms. Poor oxygenation is 
responsible for most CPAP failures. Strategies to improve oxygenation while on CPAP are needed to 
achieve a more substantial beneﬁt. A knowledge gap exists for a basic aspect of CPAP therapy: how 
much pressure should be used? While a greater airway distending pressure beneﬁts under-inﬂated lungs, 
excessive pressure may result in lung over-distension and risk harm. Strategies for determining a best 
CPAP level individualized to the needs of each premature infant are needed to help prevent BPD and 
are currently lacking (Figure 1).  Objectives: to evaluate the utility of a promising strategy for 

Page 9 of 20
individualized CPAP level selection: identifying the lowest pressure level that minimizes V/Q 
mismatch. While traditional methods for measuring V/Q mismatch are invasive or technically 
burdensome, our team has expertise in the use of a simple, non-invasive technique: a computerized 
oxygenation model enabling bedside quantiﬁcation of V/Q mismatch on the basis of the curvilinear 
characteristics generated by multiple fraction of inspired oxygen (FiO2) and peripheral oxygen 
saturation (SpO2) pairs. This technique uses data that is readily available at the infants bedside without 
a need for patient travel, additional instrumentation or blood draws, making it valuable in this 
vulnerable population. The primary speciﬁc aim of this research proposal is to measure the 
responsiveness of V/Q mismatch to a strategy of individualized CPAP level selection. In other words: 
can we detect measurable improvements in V/Q mismatch when applying a protocol for individualized 
best CPAP level selection? We hypothesize that V/Q mismatch will, on average, improve by 10% of 
baseline V/Q mismatch at the best identiﬁed CPAP level.  We will perform a phase II, single-arm 
prospective clinical trial, enrolling up to 30 premature infants of corrected gestational age 27-35 weeks, 
chronologic age greater than 24 hours and requiring supplemental oxygen while on CPAP. Infants with 
congenital anomalies or with a history of or concerns for air leak syndromes will be excluded. We will 
ﬁrst measure V/Q mismatch at baseline CPAP, set by the clinical team. Subjects will then undergo a 
protocol of stepwise CPAP level changes, with improvements in V/Q mismatch relative to baseline 
deﬁning a positive response and guiding any additional CPAP level changes. Best CPAP will be deﬁned 
as the lowest pressure level associated with a progressive response. Our primary outcome will be the 
difference in measured V/Q mismatch between baseline and best CPAP, with a paired t-test for 
parametric results or a Wilcoxon signed-rank test for non-parametric results testing our hypothesis that 
V/Q mismatch will improv
Objectives
Overall objectives
The objective of the proposed research is to evaluate a promising strategy for CPAP level selection: a 
physiologic approach minimizing V/Q mismatch and measured non-invasively at the infants bedside. 
We propose the following speciﬁc Aims and hypotheses in support of this objective:   Aim 1 (primary): 
measure the responsiveness of V/Q mismatch to a strategy of individualized CPAP level selection. We 
hypothesize that V/Q mismatch will, on average, improve by 10% of baseline V/Q mismatch at the best 
identiﬁed CPAP level. Aim 2: describe the distribution of best CPAP levels as identiﬁed by our strategy. 
Best CPAP levels will be described as both absolute values and relative to baseline (+2 cm H2O, -1 cm 
H2O, etc.). For this exploratory aim, we hypothesize that a best CPAP will be identiﬁed above the 
baseline in greater than 50% but less than 80% of subjects. Demonstrating that most but not all infants 
beneﬁt from higher pressures will highlight the importance of individualized CPAP level selection in 
premature infants.
Primary outcome variable(s)
Primary outcome measure: V/Q mismatch. This parameter will be calculated by computer software on 
the basis of the curvilinear characteristics generated by a best-ﬁt curve connecting the FiO2/SpO2 pairs 
obtained during the study protocol. With lower V/Q and greater mismatch, the curve is progressively 
displaced to the right relative to a curve corresponding to an ideal reference lung (interrupted, left-most 
curve in Figure 2, see attached documents). The V/Q ratio is displayed on the software output after the 
FiO2/SpO2 pairs are input. Additionally, this parameter is also displayed as the degree of right-shift 
relative to the ideal reference lung (greater values indicate more mismatch), providing a positive 
continuous number with units of % FiO2 as an alternative measure to the ratio value with greater ease 
of use. This will be measured twice at baseline without a change in CPAP level and then following each 
CPAP level change. The primary outcome measure is the responsiveness of V/Q mismatch to a strategy 
of individualized CPAP level selection, measured as the improvement in V/Q mismatch between the 
second baseline level and best identiﬁed CPAP level for each subject (see Figure 3 in attached 
documents.) For infants not responding to either +1 or -1 cm H2O CPAP level changes, baseline CPAP 
will be deﬁned as best, with zero assigned as the improvement in V/Q mismatch.
Secondary outcome variable(s)
Secondary outcome: best CPAP level. Our second Aim is to describe the distribution of best CPAP 
levels as identiﬁed by our strategy. We hypothesize that best CPAP will vary between infants, resulting 
in a distribution of values. Best CPAP level will be identiﬁed as the lowest CPAP level associated with 
an improvement greater than 5% in V/Q mismatch relative to the preceding CPAP level, as described in 
the study protocol. This will be "measured" once at the conclusion of the study protocol. Excessive 

Page 10 of 20
airway pressures can result in lung over-distension and can plausibly result in adverse cardiopulmonary 
interactions through transmission of positive pressure to the heart and intra-thoracic vessels (however, 
this has not been observed in any modern CPAP level studies performed in premature infants, see Table 
1). We will measure the impact of CPAP level changes on the following readily available clinical 
cardiovascular parameters during the study protocol: Mean arterial blood pressure will be measured 
with a neonatal blood pressure cuff used for routine clinical care and placed on an upper extremity or 
through pressure transduction of an indwelling arterial catheter, when present (uncommon in our 
subject population), with units of mm Hg. This outcome will be recorded at the end of each baseline 
and CPAP level period by the research team.  Heart rate will be measured and displayed by the study 
pulse oximeter, with units of beat per minute. This outcome will be recorded at the end of each baseline 
and CPAP level period by the research team.  Additional data to be collected will include: i) 
demographic data; (gestational age, birth weight, gender, race, etc.) ii) baseline variables (receipt of 
antenatal steroids, Apgar scores, age in hours and FiO2 at intervention, most recent hemoglobin level, 
CPAP pressure source and interface, etc.) and iii) important or pertinent in-hospital neonatal outcomes 
(survival to discharge, BPD, brain injury by ultrasound, patent ductus arteriosus, necrotizing 
enterocolitis, retinopathy of prematurity, duration of: MV days, CPAP and supplemental oxygen, etc). 
This data will be used to explore associations between these variables and both a) baseline V/Q 
mismatch and b) the responsiveness of this parameter to CPAP level changes, with a goal of supporting 
hypothesis generation for subsequent research
Background
Bronchopulmonary dysplasia (BPD) is a chronic lung disease resulting from premature birth that affects 
nearly 70% of infants born 28 weeks gestational age (GA) (1). BPD and its precursor, respiratory 
distress syndrome (RDS), are a leading cause of death in very premature infants (2). In turn, survivors 
require increased health expenditures and have adverse long-term respiratory and developmental 
outcomes in childhood (3-5). Despite the signiﬁcant burden of BPD on pediatric health, very few 
preventive interventions exist (6). Of these, a strategy of minimizing mechanical ventilation (MV) with 
preferential initial nasal continuous positive airway pressure (CPAP) is the most novel (7-8). CPAP 
provides a continuous distending airway pressure, maintaining lung volumes and preventing atelectasis 
(a reduction in or collapse of the air sacs responsible for gas exchange) (9-10). This improves 
oxygenation by: a) reducing ventilation/perfusion (V/Q) mismatch (inefﬁcient matching of lung areas 
receiving fresh air for gas exchange (ventilation) with lung areas receiving blood (perfusion) for gas 
exchange) and b) intrapulmonary shunt (blood passing from the right side of the heart through the lungs 
and to the body without any gas exchange). Sometimes, two levels of alternating pressure are applied in 
this way, with the higher and lower pressure levels alternating. This is called bi-level non-invasive 
support. When there is only one pressure level, this is the CPAP level. In bi-level support, the lower 
pressure level is considered the CPAP level. CPAP helps prevent BPD by providing these physiologic 
beneﬁts while avoiding MV and subsequent ventilator induced lung injury (VILI), a key component in 
the pathogenesis of BPD. However, the beneﬁt of preferential CPAP is modest. It is estimated that 1 
death or case of BPD is averted per 25 treated infants (7-8). Consistent with this limited beneﬁt, 
46-83% of very premature infants at highest risk of BPD fail initial CPAP and nonetheless require MV 
(11-12). Oxygenation failure the result of excessive V/Q mismatch and shunt is the most frequent cause 
(12-14). An improved application of CPAP resulting in less oxygenation failure would further reduce 
death or BPD.  A critical knowledge gap exists for a basic aspect of CPAP therapy: how much pressure 
should be used? There is a lack of evidence informing this question. Multi-center trials assessing CPAP 
versus MV have used pressures as disparate as 4-8 cm H2O and have not speciﬁed how these were 
determined (11, 12, 15). While higher pressures applied to under-inﬂated lungs likely improve 
oxygenation, excessive pressure may result in over-distension, increasing the risk of harms such as air 
leak syndromes (12) or adverse cardiopulmonary interactions (16). We propose evaluating a novel 
physiologic approach for individualized CPAP level selection: identiﬁcation of the lowest pressure level 
minimizing V/Q mismatch, a key contributor to poor oxygenation and CPAP failure. While traditional 
methods for measuring V/Q mismatch are invasive or technically burdensome (17-18) , our research 
team has expertise in the use of a simple, non-invasive technique: a computerized oxygenation model 
enabling bedside quantiﬁcation of V/Q mismatch (detailed within Methods) (19). In published research 
using this technique, our research team recently demonstrated a signiﬁcant association between 
gestational age and the degree of V/Q mismatch, as well as high inter-rater reliability and validity with 
this approach for predicting BPD (20-21). Identiﬁcation and application of an optimal pressure level by 
targeting a reduction in V/Q mismatch may improve oxygenation, decrease CPAP failure, avoid 
injurious MV and further reduce death or BPD (see Figure 1 in attached documentation).  Table 1 
summarizes existing prospective studies assessing the impact of CPAP level changes in premature 

Page 11 of 20
infants over the last 20 years.
Study Design
Phase*
Phase II
Design
Phase II, single-arm prospective clinical trial. The goal of a phase II clinical trial is to determine 
whether an intervention has a biologic effect and to monitor safety. In our proposal the intervention is a 
strategy of individualized CPAP level selection and the biologic effect is a response in V/Q mismatch. 
Please see Risk/Beneﬁt section for a complete discussion of safety considerations.
Study duration
Estimated length of time to enroll all subjects and complete the study: 10-12 months (please see Figure 
4 in attached documentation for a diagram describing expected enrollment).  Length of a subject's 
participation time in study: each subject will participate in activity study procedures for 60-120 
minutes. Each study will participate in the study from the time of enrollment through hospital 
discharge.  The projected dates of the proposed study, from IRB approval to data analysis and 
manuscript preparation are November 2016 to January 2018. Projected dates of active subject 
enrollment are January 2017 to November 2017. Please see Figure 5 for a project timeline.
Resources necessary for human research protection
Describe research staff and justify that the staff are adequate in number and qualiﬁcations to conduct 
the research. Describe how you will ensure that all staff assisting with the research are adequately 
informed about the protocol and their research related duties. Please allow adequate time for the 
researchers to conduct and complete the research. Please conﬁrm that there are adequate facilities for 
the research.
This study is feasible as we have the patient population, equipment and expertise to undertake the study 
if adequately supported. We have secured partial funding and are awaiting a second funding decision. 
The budgetary needs are primarily for a respiratory therapist trained to be hired as a clinical research 
coordinator. We will work with the clinical research support ofﬁce (CRSO) at the Children's Hospital of 
Philadelphia to identify and hire a speciﬁc individual in a timely fashion upon award notiﬁcation. The 
clinical research coordinator will take assume the responsibilities of daily screening and enrollment of 
the study population, communication with and between the clinical team, research team and the IRB, 
implementation of the study interventions and data collection and management. An allotment of 
adequate time to complete the research is detailed in Figure 5 (attached documents). There are adequate 
facilities for the research. The equipment necessary for conducting the study is used in the routine 
clinical practice of the HUP ICN, PAH ICN, and the CHOP N/IICU. This equipment includes pulse 
oximeters, continuous positive airway pressure generating devices and nasal interfaces, blood pressure 
cuffs and pressure transducers and cardio-respiratory monitors. All study interventions are simple 
maneuvers performed in daily clinical practice. Only the timing and sequence of their implementation 
require additional basic training. Dr. Bamat will lead the project implementation and training. Dr. 
Bamat, Dr. Handley and a respiratory therapist trained as a clinical research coordinator will perform 
the study interventions. Regular research meetings with all participating staff will ensure full 
understanding of the protocol and all research related duties.
Characteristics of the Study Population
Target population
Premature infants requiring supplemental oxygen while on CPAP or bi-level non-invasive respiratory 
support in the HUP ICN, PAH ICN, or the CHOP N/IICU.
Subjects enrolled by Penn Researchers
30

Page 12 of 20
Subjects enrolled by Collaborating Researchers
0
Accrual
This study will enroll up to 30 patients in order to evaluate 20 subjects. Infants will be screened for 
eligibility by the research team using routinely available clinical data from the electronic health record. 
Informed consent will be obtained from parents or guardians approached within the HUP ICN, PAH 
ICN, or the CHOP N/IICU during the eligibility window as described below. The diagram depicted in 
Figure 4 summarizes expected enrollment in consideration of our eligibility criteria and additional 
barriers to successful recruitment and study application. This estimate suggests a 10-month window of 
active enrollment will be required to meet our recruitment goals, making our one-year recruitment goal 
feasible.  Aim 1 guides sample size considerations. Using a paired test of correlated means, a sample 
size of 20 evaluated infants will provide 80% power to detect an overall average percent change of 10% 
from baseline, assuming a 15% standard deviation of the difference and a two-sided alpha level of 0.05.
Key inclusion criteria
I1. 27-35 weeks corrected gestational age (CGA) by best obstetric estimate, determined by the clinical 
obstetric team during antepartum admission and chronologic age, measured from date of birth  I2. 
Chronologic age greater than 24 hours, measured from time of birth.  I3. On CPAP support between 4-8 
cm H2O for greater than 24 hours, as document on the bedside infant ﬂow sheet.  I4. Supplemental 
oxygen requirement, with a fraction of inspired oxygen (FiO2) 0.25 for at least 2 consecutive hours, as 
documented on the bedside infant ﬂow sheet. (Infants without an oxygenation requirement are unlikely 
to have signiﬁcant V/Q mismatch. Further, FiO2 titrations (see Procedures) are required to apply the 
non-invasive technique, resulting in limited applicability to infants with little or no supplemental 
oxygen requirement).
Key exclusion criteria
E1. Congenital anomalies, as determined by the clinical supervising physician.  E2. Current or prior air 
leak syndrome, as determined by the clinical supervising physician.
Vulnerable Populations
x Children Form
Pregnant women (if the study procedures may affect the condition of the pregnant woman or 
fetus) Form
x Fetuses and/or Neonates Form
Prisoners Form
Other
None of the above populations are included in the research study
The following documents are currently attached to this item:
There are no documents attached for this item.
Populations vulnerable to undue inﬂuence or coercion
We recognize that the participants of this study are neonates and therefore a vulnerable population. 
However, informed consent will be obtained from legal guardians able to understand and evaluate the 
risks and beneﬁts of participation in this trial. This is to be done in both verbal and written form. Only 
parents with English as their native language will be approached. Surrogate consent from the legal 
guardian will be obtained only after efforts are made to ensure full comprehension of the study 
protocol. Furthermore parents will be reassured that there will be no repercussions in case of refusal. 
Parents will also be ensured that the persons obtaining consent will not be directly responsible for 
clinical care of the patient at that time.
Subject recruitment
All candidates for inclusion will come from the Intensive Care Nurseries (ICN) at the Hospital of the 
University of Pennsylvania, Pennsylvania Hospital, or the newborn/infant intensive care unit at CHOP. 
Their potential for enrollment is based on information routinely gathered as part of their clinical care. 
For all identiﬁed candidate subjects, the research team will contact the attending physician to discuss 

Page 13 of 20
appropriateness and safety of patient participation; the attending physician will be given the opportunity 
to deny participation at their professional discretion.
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does 
the study team plan to directly use social media to recruit for the research?
No
The following documents are currently attached to this item:
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Subject compensation*
Will subjects be ﬁnancially compensated for their participation?
No
The following documents are currently attached to this item:
There are no documents attached for this item.
If there is subject compensation, provide the schedule for compensation per study visit or session 
and total amount for entire participation, either as text or separate document
Study Procedures
Suicidal Ideation and Behavior
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)?
No
Procedures
The Non-Invasive V/Q Mismatch and Shunt Technique: A non-invasive computerized technique that 
quantiﬁes V/Q mismatch and shunt has been developed and provides a unique opportunity for research 
in premature infants. The technique can be applied using oxygenation data readily available at the 
bedside without travel outside of the HUP ICN, PAH ICN, or the CHOP N/IICU, additional 
instrumentation or phlebotomy. This is particularly valuable in premature infants requiring continuous 
monitoring in a specialized hospital environment and at high risk of frequent phlebotomy contributing 
towards anemia and a subsequent need for blood transfusions. The technique characterizes the 
relationship between FiO2 and peripheral oxygen saturation (SpO2) (see Figure 2 in attached 
documentation). Step-wise changes in delivered FiO2 result in changes in SpO2 measured by non-
invasive pulse oximetry, a standard of care monitoring device. Multiple paired values of FiO2 and SpO2 
are then plotted graphically. A computer program (22) connects the pairs by overlying a best-ﬁt curve. 
The primary impairments of gas exchange accounting for oxygenation failure in premature infants - V/
Q mismatch and shunt - have predictable effects on the shape of the curve relative to an ideal reference 
lung (interrupted, left-most curve in Figure 2). A progressive right shift of the curve is noted as V/Q 
mismatch worsens, while a progressive depression of the curve is noted as shunt worsens. In other 
words, the degree of V/Q mismatch is characterized by the relative right-shift in the position of the up-
slope of the curve, while the degree of shunt is characterized by the position of the plateau of the curve. 
Avoidance of oxygen toxicity in premature infants generally limits routine clinical SpO2 targeting to a 
maximum of 95% (23). For infants without notable shunt, reliable characterization of the plateau of the 
curve, and quantitative estimation of shunt, requires targeting multiple SpO2 values in excess of 95% - 
an unjustiﬁed risk in this population. In contrast, the position of the up-slope of the curve is well 
characterized by assessing SpO2 values between 85-95%. This curvilinear characteristic thus provides a 
quantitative measure of V/Q mismatch that can be measured at the bedside, and alternatively quantiﬁed 
as the degree of right shift from the ideal reference lung curve, with units of % FiO2.  Study Protocol: 
Prior to initiation of the study protocol, the following criteria will be met to prioritize patient safety: 1. 

Page 14 of 20
No active consideration of endotracheal intubation; as determined by the clinical Attending of record. 2. 
No hemodynamic instability, deﬁned as a baseline heart rate less than 100 beats per minute (bpm) or 
greater than 180 bpm; or a mean arterial blood pressure of less than 30 millimeters of mercury (mm 
Hg). 3. No supplemental FiO2 requirement greater than 0.45. 4. No capillary/arterial partial pressure of 
carbon dioxide greater than 65 mm Hg on last blood gas analysis, unless performed more than 6 hours 
prior. 5. No more than 6 apnea/bradycardia/desaturation events requiring tactile stimulation or more 
than 1 requiring positive pressure bag ventilation in the preceding 6 hours. Initiation of the study 
protocol will be deferred until these criteria are met.  Figure 3 depicts the study protocol as applied in 
one hypothetical subject. Of note, the protocol will vary between subjects with respect to the direction 
and extent of CPAP level changes, as determined by the absence or presence of a response at each step-
wise CPAP level change. This is described in detail below. Subjects will undergo the study interventions 
in their routine clinical environment. The clinically selected CPAP interface and pressure source will be 
maintained. A study pulse-oximeter, with low motion artifact and a short averaging time, will be placed 
on a post-ductal limb and used for SpO2 measurements. V/Q will ﬁrst be measured on two separate 
occasions 30 minutes apart at baseline CPAP, set by the clinical team. The repeat baseline measures will 
allow an estimate of the stability of V/Q as a function of time (further discussed in Confounding under 
Analysis Plan). To measure V/Q mismatch, gradual changes in delivered FiO2, followed by SpO2 
measurement, will be applied to obtain three FiO2/SpO2 pairs, one each for SpO2 values in the ranges 
of 85-87%, 89-91% and 93-95%. To obtain each SpO2 range, FiO2 will be titrated gradually until SpO2 
falls within the desired values. After 60 seconds of stabilization at the identiﬁed FiO2 value, SpO2 will 
be recorded every 30 seconds for 2 minutes if an adequate signal waveform is present, providing up to 
four SpO2 values. These values will be averaged to calculate the SpO2 value used for the FiO2/SpO2 
pair, acknowledging the inherent instability of pulse-oximeter values over time in premature infants. A 
computer software program will immediately calculate V/Q from the identiﬁed FiO2/SpO2 pairs at the 
bedside. Next, CPAP will be increased by +1 cm H2O. A period of 15 minutes will elapse to allow 
equilibration of lung volumes in response to the CPAP level change (24). V/Q calculations as described 
above will be repeated. A positive response will be deﬁned as an improvement in V/Q at the new 
pressure level of 5% relative to the preceding CPAP level. Responders will undergo subsequent 
stepwise +1 cm H2O increases up to +3 cm H2O from baseline or 8 cm H2O; whichever is less. Infants 
not responding to the initial +1 cm H2O increase will return to baseline CPAP for 15 minutes and then 
be assessed at -1 cm H2O from baseline. Infants responding at this lower CPAP level will undergo an 
additional decrease to -2 cm H2O from baseline or 3 cm H2O; whichever is greater. The allowed range 
of -2 to +3 cm H2O reﬂects our institutional practice of typically setting a baseline CPAP level of 5 or 6 
cm H2O and a CPAP pressure range of 4 to 8 cm H2O used in international trials. Best CPAP will be 
deﬁned as the lowest (and last) CPAP level at which a positive response, as deﬁned above, is measured. 
The baseline CPAP level will be deﬁned as best for those infants not responding to either +1 or -1 cm 
H2O CPAP level changes, with a corresponding V/Q improvement of zero. Upon completion of the 
study protocol, infants will be returned to their baseline CPAP level. The study protocol will typically 
require between 60 and 120 minutes. Throughout the study, a set of pre-deﬁned stopping criteria will be 
monitored to ensure subject tolerance of the study procedures. These criteria are designed to be 
conservative safety measures and will result in study termination and provision of supportive care, as 
needed.  Patient Safety Considerations:  Extensive patient safety considerations minimizing the risks 
associated with implementation of this phase II design research protocol have been incorporated:  1. 
Many of the key eligibility (inclusions and exclusion) criteria reﬂect the deliberate selection of a 
premature infant population that is inherently less vulnerable and at lower risk of common morbidities 
of prematurity and less likely to suffer any adverse outcomes from implementation of the study 
procedures. a). I1. Corrected gestational age 27-35 weeks (GA): this selects a study population in which 
respiratory distress syndrome is common and CPAP is frequently used, while avoiding less mature 
infants with a CGA less than 27 weeks who are more prone to physiologic instability. We exclude this 
population in consideration of safety for this phase II study despite a high risk of CPAP failure and a 
potential for beneﬁt from our long-term research goals of establishing methods to prevent CPAP failure.  
b) I2. Chronologic age of greater than 24 hours. This avoids study of infants during the ﬁrst 24 hours of 
life when they may be more prone to physiologic instability.  c) I3. On continuous CPAP support for 
greater than 24 hours. This prioritizes safety by restricting study to subjects demonstrating stability on 
CPAP therapy, in contrast to infants newly transitioned to CPAP without a period of demonstrated 
tolerance. d) I4. Supplemental oxygen requirement, with a fraction of inspired oxygen (FiO2) 0.25 for 
at least 2 consecutive hours. This ensures that CPAP level changes are only performed in infants 
requiring supplemental oxygenation, suggesting V/Q mismatch and/or shunt from atelectasis. These 
subjects would plausibly beneﬁt from carefully monitored changes in continuous distending airway 
pressure to counteract the pathophysiology resulting in the oxygen need. This criteria avoids CPAP 

Page 15 of 20
level changes in infants on CPAP but not requiring supplemental oxygen as they are less likely to 
beneﬁt from changes in pressure level.  e) E2. Exclusion of infants with current or prior air leak 
syndrome. This avoids study in infants with suggestion of a pathophysiology that could worsen with 
increased CPAP levels. 2. To further avoid study in infants with physiologic instability, the following 
criteria will be met prior to initiation of the study procedures; with deferral of the study until they are 
met:  a. No active consideration of endotracheal intubation; as determined by the clinical Attending of 
record.  b. No hemodynamic instability, deﬁned as a baseline heart rate less than 100 beats per minute 
(bpm) or greater than 180 bpm; or a mean arterial blood pressure of less than 30 millimeters of mercury 
(mm Hg).  c. No supplemental FiO2 requirement greater than 0.45.  d. No capillary/arterial partial 
pressure of carbon dioxide greater than 65 mm Hg on last blood gas analysis, unless performed more 
than 6 hours prior.  e. No more than 6 apnea/bradycardia/desaturation events requiring tactile 
stimulation or more than 1 requiring positive pressure bag ventilation in the preceding 6 hours. 3. 
Stepwise changes in CPAP level, with assessment after each CPAP level change and restriction of 
further pressure changes to instances in which there is a response suggestive of improving physiology - 
deﬁned as greater than a 5% improvement of baseline V/Q mismatch. Infants who are at inadequate 
lung volumes at baseline CPAP are likely to show beneﬁt with higher pressure levels, while infants with 
adequate lung volumes at baseline CPAP are unlikely to show any physiologic beneﬁt at higher pressure 
levels. Similarly, infants with over distended lung volumes at baseline may beneﬁt from lower pressure 
levels, while infants with adequate lung volumes at baseline CPAP are unlikely to show beneﬁt with 
lower pressure levels. This key element of study procedures will protect against the risk of over-
distension or loss of lung volumes secondary to the study procedures. 4. Stopping Criteria. The 
following "stopping criteria" will be monitored in each subject throughout the study procedures and will 
result in study termination, provision of supportive care and a return to baseline settings when 
appropriate:  a) a drop in mean arterial pressure to a mmHg value less than 30 mm Hg and in excess of 
10% from the baseline value, or in excess of 20% of baseline value.  b) an increase in heart rate to 
greater than 190 bpm and in excess of 10% from the baseline value or in excess of 20% of the baseline 
value. c) with an adequate pulse waveform, a sustained drop in SpO2 to less than 80% for greater than 
one minute or a drop in SpO2, to less than 75% for greater than 30 seconds or less than 45% for any 
duration of time.  d) a two-fold increase in the hourly frequency of cardiorespiratory events (apnea/
bradycardia/desaturation) relative to the average frequency in the four hours prior to study initiation. 
For infant without any events in the four hours prior to study initiation, greater than one event per hour 
will be used as a threshold. Further, any single event requiring bag- mask positive pressure ventilation 
will lead to study termination.
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Deception
Does your project use deception?
No
International Research
Are you conducting research outside of the United States?
No
Analysis Plan
Results will be summarized using basic descriptive statistics. For Aim 1, a paired t-test for parametric 
results or a Wilcoxon signed-rank test for non-parametric results will be used to test our hypothesis that 
V/Q mismatch will improve at best CPAP level compared to baseline. For Aim 2, we will calculate the 
proportion of subjects in which best CPAP level is identiﬁed above the baseline pressure level to assess 
our hypothesis that this occurs in greater than 50% but less than 80% of subjects. Further, best CPAP 
for the cohort will be summarized as mean and standard deviation (if parametric) or median and 
interquartile range (if non-parametric). No formal statistical testing of signiﬁcance will be performed 
for this second descriptive Aim. The change in V/Q over the two baseline periods, as well as the change 
in heart rate and blood pressure between baseline and best CPAP levels will be tested using the 
statistical approach as Aim 1. We predict the null hypothesis of no signiﬁcant difference for these 
comparisons. Should a signiﬁcant change in V/Q be identiﬁed between baseline periods, we will 
perform an additional analysis comparing the change in V/Q between baseline periods to the change in 
V/Q between baseline and best CPAP level to account for the independent impact of time on V/Q 

Page 16 of 20
mismatch.  Confounding: key elements of our study design limit confounding for Aim 1, to measure the 
responsiveness of V/Q mismatch to a strategy of individualized CPAP level selection. The use of a pre-
post within-patient analysis limits confounding from variation in between-patient characteristics. A 
remaining important source of confounding is the possibility that V/Q simply improves over time 
irrespective of CPAP pressure changes. We account for this by measuring V/Q on two separate 
occasions 30 minutes apart at baseline CPAP in the study protocol, facilitating an assessment of the 
stability of V/Q over time.
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Data conﬁdentiality
x Paper-based records will be kept in a secure location and only be accessible to personnel involved 
in the study.
x Computer-based ﬁles will only be made available to personnel involved in the study through the 
use of access privileges and passwords.
x Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and conﬁdentiality of identiﬁable information.
x Wherever feasible, identiﬁers will be removed from study-related information.
A Certiﬁcate of Conﬁdentiality will be obtained, because the research could place the subject at 
risk of criminal or civil liability or cause damage to the subject's ﬁnancial standing, 
employability, or liability.
A waiver of documentation of consent is being requested, because the only link between the 
subject and the study would be the consent document and the primary risk is a breach of 
conﬁdentiality. (This is not an option for FDA-regulated research.)
Precautions are in place to ensure the data is secure by using passwords and encryption, because 
the research involves web-based surveys.
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identiﬁcation of subjects.
Subject Conﬁdentiality
Several strategies will be employed to maintain conﬁdentiality of identiﬁable data and to adequately 
protect patient privacy. Use of identiﬁable private information will be limited to consent documentation 
and a study enrollment log. The study enrollment log will link the patient information to a unique 
patient study ID. This ID will be used in all other paper-based and computer-based ﬁles. Paper-based 
records will be scanned and made into PDFs following completion of each subject's protocol. 
Destruction of paper-based records will occur at the completion of the study. Only study personnel will 
have access to computer based ﬁles, which will be maintained within an institutionally secured and 
managed network drive  or an institutionally secured & managed device within the ofﬁces of the 
Division of Neonatology. The study enrollment log linking patient identiﬁable information to other data 
will be destroyed within 5 years of study completion. Data will not be shared with non-study personnel.
Sensitive Research Information*
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record?
No
Subject Privacy
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas conﬁdentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). 
The nature of the research study will not result in any substantial additional risk to patient privacy. 

Page 17 of 20
Patient families will be contacted by telephone via phone calls or text only using numbers designated 
by them at the time of admission to the HUP ICN, PAH ICN, or the CHOP N/IICU. Families will not 
be physically approached about the research study nor have the research study discussed with them 
outside the conﬁnes of the HUP ICN, PAH ICN, or the CHOP N/IICU. Whenever possible, 
communication will occur in person rather than over telephone. Collection of personal health 
information will be limited to that necessary to facilitate the collection of study data and will be 
codiﬁed into a patient study ID and safeguarded as described above.
Data Disclosure
Will the data be disclosed to anyone who is not listed under Personnel?
No
Data Protection*
x Name
Street address, city, county, precinct, zip code, and equivalent geocodes
x All elements of dates (except year) for dates directly related to an individual and all ages over 89
x Telephone and fax number
Electronic mail addresses
Social security numbers
x Medical record numbers
Health plan ID numbers
Account numbers
Certiﬁcate/license numbers
Vehicle identiﬁers and serial numbers, including license plate numbers
Device identiﬁers/serial numbers
Web addresses (URLs)
Internet IP addresses
Biometric identiﬁers, incl. ﬁnger and voice prints
Full face photographic images and any comparable images
Any other unique identifying number, characteristic, or code
None
Does your research request both a waiver of HIPAA authorization for collection of patient information 
and involve providing Protected Health Information ("PHI") that is classiﬁed as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a 
recipient outside of the University of Pennsylvania covered entity?
No
Tissue Specimens Obtained as Part of Research*
Are Tissue Specimens being obtained for research?
No
Tissue Specimens - Collected during regular care*
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)?
No
Tissue Specimens - otherwise discarded*
Would specimens otherwise be discarded?
No

Page 18 of 20
Tissue Specimens - publicly available*
Will tissue specimens be publicly available?
No
Tissue Specimens - Collected as part of research protocol*
Will tissue specimens be collected as part of the research protocol?
No
Tissue Specimens - Banking of blood, tissue etc. for future use*
Does research involve banking of blood, tissue, etc. for future use?
No
Genetic testing
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision 
of genetic counseling. Describe how subject conﬁdentiality will be protected Note: If no genetic testing 
is to be obtained, write: "Not applicable."
Not applicable
Consent
1. Consent Process
Overview
We will obtain informed consent from both parents unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only one parent has legal responsibility for the care 
and custody of the child. Informed consent will be obtained by direct communication and interaction 
between a member of the research team and the parents or legal guardians of the infant while present at 
the HUP ICN, Pennsylvania Hospital ICN, or the CHOP N/IICU. Written information regarding the 
nature of the study will be initially provided to the parents or guardians, as well as further information 
face-to-face. This information handout will be written in non-medical language, and will explain the 
voluntary and non-binding nature of participation in the study, the relevance of the study, the objective 
of the study, the study procedures, potential risks and that participation will not change the standard 
course of care. It will also explain the steps that will be taken to ensure privacy and conﬁdentiality. We 
will ensure that the parents or guardians are able to read and comprehend the handout. All materials will 
be written in a 8th grade reading level. As the exclusion criterion indicates, we will not enroll those who 
are not English speakers. Following sufﬁcient time for the handout to be read and comprehended, a 
member of the treatment or research team will approach the parents or guardians to obtain informed 
consent. We will ensure that the parents or guardians understands the contents of the handout and allow 
them to ask any questions or concerns, which will be fully addressed. Prior to signing the consent form, 
a member of the treatment team will summarize the central components of the study and consent 
process, and verify understanding of the consenting parties. Following obtaining of the informed 
consent, the parents or guardians will be reminded of the voluntary and non-binding nature of the 
consent and reminded that they may withdraw support at any time. The parents or guardians will be 
approached and the consent process will be performed within the physical boundaries of the HUP ICN, 
PAH ICN, or the CHOP N/IICU. An assessment by the research team interacting with the parents or 
guardians will determine if they are competent to provide consent, for instance if literacy or language 
barriers prevent the parents or guardians from being able to read the provided documentation.
Children and Adolescents
Not applicable
Adult Subjects Not Competent to Give Consent
An assessment by the research team interacting with the parents or guardians will determine if they are 
competent to provide consent, for instance, if literacy or language barriers prevent the parents or 
guardians from being able to read the provided documentation. Otherwise, not applicable.

Page 19 of 20
2. Waiver of Consent
Waiver or Alteration of Informed Consent*
No Waiver Requested
Minimal Risk*
Impact on Subject Rights and Welfare*
Waiver Essential to Research*
Additional Information to Subjects
Written Statement of Research*
No
If no written statement will be provided, please provide justiﬁciation
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Risk / Beneﬁt
Potential Study Risks
Potential study risks are limited to the physiologic risks associated with changing CPAP and inspired 
supplemental oxygen. No direct psychological, social, economic, monetary, legal, or those risks that 
result from a loss of conﬁdentiality is in any way anticipated. With respect to the physiologic risks 
associated with changing CPAP and FiO2, several study design elements minimize the risk for harm in 
this phase II study. They are extensively detailed within "Patient Safety Considerations" in the 
"Procedures" section of this application. In summary, the eligibility criteria select a population in whom 
the study objectives are relevant, but who are less vulnerable to injury than extremely premature infants. 
The principal risks associated with the study procedures are those associated with over and under-
distension of the lungs with CPAP level changes and the possibility of transient hypoxia and hyperoxia 
during FiO2 changes. The former are minimized by the gradual step-wise changes in CPAP, ensuring 
that additional pressures are only tested when there is suggestion of improving physiology, and an 
evaluation restricted to a typical CPAP level range of 3 to 8 cm H2O. Previous CPAP level trials in 
premature infants have studied levels as low as 0 cm H2O and as high as 9 cm H2O without reported 
concerns for harm (See Table 1). The latter will be limited by careful adherence to an accepted SpO2 
target range. Additional safety criteria to be veriﬁed immediately prior to application of the study 
interventions and comprehensive safeguards to protect against adverse events during the study 
interventions are described within "Procedures"  Further, with respect to the physiologic risks imposed 
by the CPAP and FiO2 changes, the likelihood and seriousness of these risks are minimal for the 
following reasons: 1. The CPAP levels evaluated reﬂect those used in routine clinical practice and levels 
assessed in international trials of CPAP therapy.  2. The CPAP level changes are transient and of short 
duration; the baseline clinical CPAP level is returned to at study termination.  3. The tested SpO2 levels 
will be within 85-95%, the range consistent with acceptable target SpO2 levels in international clinical 
practice.  4. A member of the research team will remain at the bedside throughout the study procedures, 
ensuring a greater degree of oxygen titration to target saturation levels than is often possible in routine 
clinical care. 5. All prior studies (Table 1) using CPAP level changes similar to and in times in excess of 
the range proposed in this study have either not reported concerns for adverse events or reported a lack 
of signiﬁcant increase in adverse events as a result of study.
Potential Study Beneﬁts
1. Individual subject: A. We do not expect direct patient beneﬁt from the study intervention as the 
intervention is not applied with a therapeutic intent but to measure changes in physiological responses 
and all subjects included in the study may not experience/need lung re-recruitment. For infants in need 
of lung re-recruitment, the study procedure could potentially serve as a carefully monitored lung 
recruitment maneuver, guided by improvements in V/Q mismatch. In infants for whom the 

Page 20 of 20
supplemental oxygen need required for study inclusion reﬂects atelectasis, study participation may 
recruit atelectactic lung that remains ventilated despite a subsequent return to baseline CPAP levels. The 
potential beneﬁt of lung recruitment maneuvers of this type - with temporary increases in continuous 
distending pressure followed by a return to a lower pressure resulting in sustained beneﬁt - is supported 
by recent neonatal literature in infants on positive end expiratory pressure (25-26).  B. We do not 
propose to maintain infants on best CPAP as deﬁned in this protocol. However, the information gained 
during through the study procedures will be shared with the clinical team. Information regarding the 
oxygenation response to changes in CPAP level in a speciﬁc infant are of clear clinical interest, but are 
rarely obtained due to the time and personnel resources required for careful measurement. The study 
procedures provides this information, which may be considered by the clinical team together with many 
additional factors when making clinical judgements. 2. There are beneﬁts that may accrue to society for 
future premature infants newborns through completion of this study. These are considerable as they 
would help in deﬁning respiratory management strategies for newborn care, an area of considerable 
morbidity in this population.
Alternatives to Participation (optional)
We will include the following language in the informed consent: "If you choose not to participate in this 
study, your baby will continue to receive the usual clinical care provided in the HUP ICN, PAH ICN, or 
the CHOP N/IICU. The alternative to enrolling your child in this study is not to participate. No negative 
consequences will result from choosing not to participate in the study."
Data and Safety Monitoring
Safety and privacy will be ensured as stated previously in Study Procedures, Conﬁdentiality, Subject 
Privacy/ Protected Health Information and Potential Study Risks. A committee compromised of the 
research team and two additional neonatologists not directly involved in the study will meet to review 
safety data after 7 and 14 subjects are enrolled.  We will document the proportion of subjects requiring 
early study termination on the basis of these stopping rules, with an expectation of less than 20% of 
enrolled subjects. Safety monitoring following application of the study protocol will include monitoring 
for air leak syndromes (pneumothorax, pulmonary interstitial emphysema, pneumomediastinum; as 
determined by the clinical supervising physician during routine clinical care) and respiratory 
deterioration, deﬁned as an increase in baseline FiO2 greater than 0.10 in the 48 hour following the 
study intervention, excluding infants in whom the rate of rise in FiO2 prior to study interventions 
demonstrates a comparable FiO2 trend. We anticipate these outcomes in no more than 10% of enrolled 
subjects.
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Risk / Beneﬁt Assessment
As previously described, many considerations to minimizing risk have been taken in the study 
procedures. The risk incurred from participating in the study is small; the protocol only deviates from 
standard of care practices in the HUP ICN, PAH ICN, or the CHOP N/IICU by changing CPAP and 
FiO2 levels. The changes are within the range used in neonatal clinical practice and implemented for 
short periods of time. The infants will be monitored closely for any physiologic instability suggestive of 
possible evolving harm through a set of conservative "stopping rules" providing an opportunity to 
terminate the study and prevent harm. The study's potential beneﬁt to society, as described above, 
justiﬁes the small risk posed to the recruited subjects.
General Attachments
The following documents are currently attached to this item:
Additional forms (woodfordgcp20191231.pdf)
Additional forms (woodfordhumansubjects20210924.pdf)
Cover Letter (cpapvqmodiﬁcationcoverletter2.20.19.doc)