A Multi-center Randomized Controlled Trial of Respiratory Function Monitoring During Stabilization of Preterm Infants at Birth
Phase: NA
Conditions: Resuscitation, Neonatal Prematurity, Positive-Pressure Respiration
Sponsor: University of Pennsylvania

 
Study Title: A randomized controlled trial of respiratory function 
monitoring during stabilization of preterm infants at birth 
Short Title: MONITOR Trial 
NCT Number: NCT03256578 
Document IRB Approval Date: February 14, 2019 

 
 
MONITOR TRIAL  
(Monitoring Neonatal Resuscitation Trial) 
A multi-center randomized controlled trial of respiratory function monitoring during 
stabilization of preterm infants at birth 
 
Local Principal Investigator (1) 
Elizabeth Foglia MD MSCE1 
Division of Neonatology 
3400 Spruce St. Ravdin 8 
215-662-3228 
foglia@email.chop.edu 
 
Coordinating Site Principal Investigator (2) 
 
Arjan te Pas2  
C.Omar Kamlin3  
Prof Maximo Vento4  
Gianluca Lista5  
Kajsa Bohlin7 
Co-Investigators (3) 
 
Henriette van Zanten2  
Prof Colin Morley3  
Enrico Lopriore2  
Prof Peter G Davis3  
Marta Thio3  
Charles Christopher Röhr2  
Marta Aguar4  
Francesco Cavigioli5  
Erik van Zwet6 
 
1. Hospital of the University of Pennsylvania, Philadelphia, United States 
2. Leiden University Medical Center, Leiden, the Netherlands  
3. Department of Newborn Research, Royal Women’s Hospital, Melbourne, Australia  
4. Maternal & Children’s University Hospital La Fe, Valencia, Spain  
5. Neonatal Intensive Care Unit, V.Buzzi Children's Hospital, Milan, Italy  
6. Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands  
7. Karolinska University Hospital Huddinge, Stockholm, Sweden  
 
Protocol Version: UPenn MONITOR Protocol Version 3.0 February 5, 2019 
IRB Number: 826695 
 
Coordinating Site Protocol Version: Protocol 12.295 v5 December 8, 2017 
Netherlands Trial Registry: NTR4104 
Clinicaltrials.gov Identifier: NCT03256578 

 
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Table of Contents 
 
LIST OF ABBREVIATIONS ................................................................................................................................. IV 
STUDY SUMMARY ........................................................................................................................................... 1 
1. 
BACKGROUND AND STUDY RATIONALE........................................................................................................... 2 
1.1 
INTRODUCTION .................................................................................................................................. 2 
1.2 
BACKGROUND AND RELEVANT LITERATURE ................................................................................................. 2 
1.3 
RESPIRATORY FUNCTION MONITOR (RFM) ................................................................................................ 3 
1.4 
PRELIMINARY CLINICAL STUDIES OF RFM ................................................................................................... 3 
2. 
STUDY OBJECTIVES .................................................................................................................................. 4 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 4 
2.2 
SECONDARY OBJECTIVES ....................................................................................................................... 4 
3. 
INVESTIGATIONAL PLAN ............................................................................................................................ 4 
3.1 
GENERAL DESIGN................................................................................................................................ 4 
3.2 
SCREENING PHASE .............................................................................................................................. 5 
3.3 
STUDY INTERVENTION PHASE ................................................................................................................. 5 
3.3.1 
ALLOCATION TO INTERVENTIONAL GROUP .................................................................................................. 5 
3.4 
PRIMARY ENDPOINT ............................................................................................................................ 6 
3.5 
SECONDARY ENDPOINTS ....................................................................................................................... 6 
4. 
STUDY POPULATION AND DURATION OF PARTICIPATION ..................................................................................... 7 
4.1 
INCLUSION CRITERIA ............................................................................................................................ 7 
4.2 
EXCLUSION CRITERIA ............................................................................................................................ 7 
4.3 
SUBJECT RECRUITMENT ........................................................................................................................ 7 
4.4 
DURATION OF PARTICIPATION ................................................................................................................. 7 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES .................................................................................................... 8 
4.6 
VULNERABLE POPULATIONS: .................................................................................................................. 8 
5. 
STUDY INTERVENTION ............................................................................................................................... 8 
5.1 
DESCRIPTION ..................................................................................................................................... 8 
5.2 
SUBJECT ENCOUNTER: DELIVERY ROOM ..................................................................................................... 8 
5.3 
TRAINING ......................................................................................................................................... 9 
5.4 
BLINDING ......................................................................................................................................... 9 
5.5 
TECHNIQUE OF RESUSCITATION ............................................................................................................... 9 
5.6 
DISCONTINUATION OF MONITORING ........................................................................................................ 9 
6. 
STUDY PROCEDURES .............................................................................................................................. 10 
6.1 
SCREENING ..................................................................................................................................... 10 
6.2 
STUDY INTERVENTION PHASE ............................................................................................................... 10 
6.3 
DATA COLLECTION PHASE ................................................................................................................... 10 
6.4 
SUBJECT WITHDRAWAL ...................................................................................................................... 10 
6.5 
SAFETY EVALUATIONS ........................................................................................................................ 11 
7. 
STATISTICAL PLAN ................................................................................................................................. 11 
7.1 
BASELINE DATA ................................................................................................................................ 11 
7.2 
PRIMARY AND SECONDARY OUTCOMES ................................................................................................... 11 
7.3 
SAMPLE SIZE AND POWER DETERMINATION .............................................................................................. 11 
8. 
SAFETY AND ADVERSE EVENTS .................................................................................................................. 12 
8.1 
DEFINITIONS ................................................................................................................................... 12 

 
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8.1.1 
ADVERSE EVENT ............................................................................................................................... 12 
8.1.2 
SERIOUS ADVERSE EVENT .................................................................................................................... 12 
8.2 
RECORDING OF ADVERSE EVENTS .......................................................................................................... 13 
8.3 
RELATIONSHIP OF AE TO STUDY ............................................................................................................ 13 
8.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ................................. 14 
8.4.1 
FOLLOW-UP REPORT .......................................................................................................................... 14 
8.4.2 
INVESTIGATOR REPORTING: NOTIFYING THE PENN IRB ................................................................................. 14 
8.5 
DATA AND SAFETY MONITORING PLAN .................................................................................................... 14 
9. 
STUDY ADMINISTRATION, DATA HANDLING, AND RECORD KEEPING ..................................................................... 15 
9.1 
CONFIDENTIALITY .............................................................................................................................. 15 
9.2 
DATA AND DEVICE COLLECTION, STORAGE, AND MANAGEMENT ..................................................................... 16 
9.2.1 
STORAGE OF THE RFM ....................................................................................................................... 16 
9.2.2 
SOURCE DOCUMENTS ........................................................................................................................ 16 
9.2.3 
VIDEO RECORDINGS........................................................................................................................... 17 
9.2.4 
CASE REPORT FORMS.................................................................................................................. 17 
9.2.5 
DATA MANAGEMENT ......................................................................................................................... 17 
9.3 
RECORDS RETENTION ......................................................................................................................... 18 
10. 
ETHICAL CONSIDERATIONS ................................................................................................................... 18 
10.1 
RISKS ............................................................................................................................................ 18 
10.2 
RISK BENEFIT ASSESSMENT .................................................................................................................. 19 
10.3 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ............................................................................. 19 
10.3.1 
CO-ENROLLMENT ......................................................................................................................... 19 
10.4 
WAIVER OF ASSENT ........................................................................................................................... 20 
10.5 
FUNDING SOURCE ............................................................................................................................. 20 
10.6 
CONFLICT OF INTEREST ....................................................................................................................... 20 
10.7 
SUBJECT PAYMENTS........................................................................................................................... 20 
10.8 
PUBLICATION PLAN ........................................................................................................................... 20 
11. 
REFERENCES .................................................................................................................................... 20 
 
 
 
 
 
 
 
 
 
 
 
 

 
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List of Abbreviations 
 
BPD- Bronchopulmonary Dysplasia 
CHOP- Children’s Hospital of Philadelphia 
CRF- Case Report Form 
DR – Delivery Room 
DSMB – Data Safety Monitoring Board 
CPAP – Continuous Positive Airway Pressure 
ET- Endotracheal 
ETT – Endotracheal Tube 
FiO2 – Fraction of Inspired Oxygen 
HUP – Hospital of the University of Pennsylvania 
IR- Infant Resuscitation Room 
IRB- Institutional Review Board 
IPPV- Intermittent Positive Pressure Ventilation 
NICU- Neonatal Intensive Care Unit 
PEEP – Positive End Expiratory Pressure 
PHI – Personal Health Information 
PIP – Positive Inspiratory Pressure  
PPV – Positive Pressure Ventilation 
RFM – Respiratory Function Monitor 
SAE – Serious Adverse Event 
SAIL – Sustained Aeration of Infant Lungs (Trial) 
SI – Sustained Inflation 
SpO2 – Saturation Pulse Oximeter Oxygen Saturation 
Vte – Expired Tidal Volume 
Vti – Inspired Tidal Volume 

Monitor Trial 
 
page 1 
Version 3.0 February 5, 2019 
 
Study Summary 
Title 
 A randomized controlled trial of respiratory function monitoring during stabilization 
of preterm infants at birth 
Short Title 
Monitor Trial (Monitoring Neonatal Resuscitation Trial) 
IRB Number 
Pending 
Protocol Number 
Protocol 12.295 v4 21-09-2013 
Methodology 
Multi-center, non-blinded, randomized controlled trial 
Study Duration 
Study enrollment is expected to take 3 years, with an additional 6 months for data 
analysis and manuscript preparation 
Study Center(s) 
Hospital of the University of Pennsylvania, Philadelphia, United States 
Children’s Hospital of Philadelphia, Philadelphia, United States 
Leiden University Medical Center, Leiden, the Netherlands  
Department of Newborn Research, Royal Women’s Hospital, Melbourne, Australia  
Maternal & Children’s University Hospital La Fe, Valencia, Spain  
Neonatal Intensive Care Unit, V.Buzzi Children's Hospital, Milan, Italy  
Karolinska University Hospital Huddinge, Stockholm, Sweden  
 
Objectives 
Primary: 
To determine whether a visible respiratory function monitor display increases the 
proportion of PPV inflations performed within a predefined exhaled target tidal 
volume range of 4 – 8 mls/kg.  
Secondary: 
To determine whether visible data and waveforms displayed on an RFM impact other 
clinical, physiological, and biochemical indicators of ineffective lung aeration.  
Number of Subjects 
286 infants across 6 sites 
Main Inclusion and 
Exclusion Criteria 
Infants will be included in this study if they are (1) between 24 and 27 6/7 weeks 
gestation (2) receiving PPV for resuscitation at birth.  Exclusion criteria include (1) a 
congenital abnormality which might interfere with breathing, (2) RFM not available. 
Intervention 
In the RFM-visible group, the RFM will record respiratory parameters of all PPV 
inflations, and the RFM display will be visible to the clinical resuscitation team in 
addition to routine clinical monitoring.   
Reference Group 
In the RFM-masked group, the RFM will record respiratory parameters of all PPV 
inflations, but the RFM display will not be visible to the clinical resuscitation team.  
Routine clinical monitoring alone will be used during PPV.  
Statistical Methodology 
The Primary outcome will be analyzed as a comparison of proportion of exhaled tidal 
volumes 4-8 mls/kg between the RFM-visible and RFM-masked groups.  
Secondary outcome measures of ineffective lung aeration will be analyzed through 
mean and proportion comparisons between the RFM-visible and RFM-masked 
groups. 
Safety Evaluations  
DSMB data monitoring of the trial will occur over the first month and every 6 months. 
If the DSMB finds a difference between groups of at least 10% in mortality in the first 
week of life, the trial will be stopped. 
Data and Safety 
Monitoring Plan  
An external DSMB is comprised of three members: a trained neonatologist, a 
biostatistician, and pediatric oncologist, all with extensive experience in conducting 
trials. The DSMB will be updated in the progress of the trial every 6 months, or more 
frequently if necessary.  
 

 
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1. Background and Study Rationale 
 
This study will be conducted in full accordance all applicable University of Pennsylvania 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46 and 21 CFR Parts 50, 54, 56. 
1.1 
Introduction 
       
The transition from the fluid-filled fetal lung to the aerated lung is essential for successful 
adaptation after birth. Extremely preterm infants have an immature respiratory system and 
struggle to successfully aerate the lung.  Most extremely premature newborns require 
respiratory support with positive pressure ventilation (PPV) during this transition.  However, 
non-invasive (facemask) PPV is technically challenging to perform. Inadequate (too little) PPV 
inflation leads to ineffective ventilation and hypoxia, manifested by a lack of prompt rise in 
heart rate and progression to need for tracheal intubation.  Excessive (too large) PPV inflations 
damage the newborn lung from stretch and pressure injury.  Providers have few tools to 
identify inadequate or excessive PPV inflations.  Current delivery room technology is inadequate 
to guide PPV inflations delivered to preterm infants. 
 
This is a randomized trial to determine if a visible respiratory function monitor (RFM) displaying 
real-time measurements of delivered inflations improves clinical providers’ ability to perform 
PPV within a pre-defined target tidal volume in preterm infants after birth. 
1.2 
Background and Relevant Literature  
 
Extremely preterm infants often fail to establish efficient gas exchange independently in the 
delivery room (DR) 1,2 and many receive mask ventilation or tracheal intubation and mechanical 
ventilation.3 However, immediately after birth the immature lung is highly vulnerable to injury. 4 
As there is increasing evidence that gentle ventilation may reduce lung injury, short- and long-
term morbidity, 4-13 more effective non-invasive resuscitation strategies14 in the DR are 
required.  
 
Caregivers are guided by international and national neonatal resuscitation guidelines and a face 
mask is commonly recommended and widely used for initial ventilation after birth.15,16 A tight 
seal between mask and face creating a leak free ventilation circuit is important to provide 
positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) to the 
transitioning preterm infant.17 Leak at the mask may contribute to inadequate ventilation or 
even failure of the resuscitation.17,17-22  Achieving effective manual ventilation can be difficult 18-
22 because most clinicians are not aware when mask leak or airway obstruction occur.19,23,24 
With variable leaks, variable tidal volumes are delivered that may be either inadequate or 
excessive causing lung injury. This has been described as atelectotrauma, rheotrauma and 
barotrauma. Moreover, inadequate ventilation may lead to persistently lower oxygen 
saturations (SpO2) prompting clinicians to increase FiO2. The newly born infant’s lung is 

 
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susceptible to pro-oxidant mediated inflammation25 and administration of supplemental 
oxygen during neonatal resuscitation has recently been revised to reflect this.  
 
Traditionally, adequacy of ventilation during positive pressure ventilation (PPV) in the DR is 
assessed by adequate chest rise and an increase in heart rate.26 This contrasts with the 
assessment of optimal ventilation in the neonatal intensive care unit. Best practice guidelines 
from experts state that mechanical ventilation should be guided by a continuous display of 
airway pressure, gas flow, tidal volume (VT) and gas leak at the endotracheal tube (ETT).20-22  
 
1.3 
Respiratory Function Monitor (RFM) 
 
Recently, it has been demonstrated that the use of a respiratory function monitor (RFM) can 
guide PPV in the DR.23,27  In this study, the New Life Box, (Advanced Life Diagnostics, Weener, 
Germany) a neonatal Respiratory Monitor (RFM), will be used to measure and calculate 
inflation pressures, flow, and tidal volumes in all enrolled infants.  The New Life Box uses a 
small (dead space 0.7 mL) variable orifice anemometer to measure gas flow in and out of a 
face-mask or endotracheal tube. This signal is automatically integrated to provide inspired (Vti) 
and expired (Vte) tidal volume. The difference equals the leak from the facemask or 
endotracheal tube. Complete airway obstruction occurs when no flow of gas into or away from 
the infant is seen during a positive pressure inflation. The RFM can also calculate and measure 
respiratory rate and minute volume, inflations and spontaneous inspirations, and all ventilation 
pressures. Using customized software heart rate, oxygen saturation and expired carbon dioxide 
can be integrated into the RFM. 
 
The NewLife Box monitor presents graphical information for pressure, flow, and volume.  In 
addition, the monitor displays numeric data for pressure (PIP and PEEP), tidal volume (Vti, Vte), 
flow, respiratory rate and percent leak.  The monitor integrates and displays physiologic data 
streaming from the patient (heart rate and oxygen saturation) as well as FiO2 from an oxygen 
analyzer in the inspiratory limb of the respiratory circuit. If enabled, the monitor can 
incorporate video captured from an external camera. The video serves as a helpful aid in the 
interpretation of the events during the RFM waveform recordings. 
 
1.4 
Preliminary Clinical Studies of RFM 
 
Kattwinkel et al, showed using a mechanical model of an infant’s lung during a simulation of 
neonatal resuscitation, operators had a faster response to compliance changes if tidal volumes 
were displayed.28 Manikin and observational studies have shown that a RFM enabled the 
clinical team to quickly recognize mask leak, inadequate expired Vt, or airway obstruction. 23,27 
In addition, spontaneous breathing in newly born preterm infants is difficult to observe and 
quantitate and often missed by the clinician leading to unnecessary respiratory support or even 
intubation.29 An RFM is very useful for observing and measuring spontaneous breathing.30  
 

 
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However, thus far data from large randomized studies on the use of an RFM during neonatal 
resuscitation are lacking. Schmölzer et al, observed a reduction in mask leak, less excessive tidal 
volumes and less intubations in a small randomized feasibility trial of RFM versus no RFM 
during mask ventilation in preterm infants at birth.31 This study stressed that increasing training 
and experience in using an RFM may lead to greater benefits. Schilleman et al reported that 
clinicians in the DR did not use all the information available from RFM, but relied more on 
traditional clinical parameters.29  
 
The use of an RFM in the DR has the potential to improve neonatal respiratory support and 
reduce lung injury. To prove this, a large randomized trial is needed.  
2. Study Objectives 
 
Our hypotheses are that using a RFM during PPV resuscitation of infants at birth will lead to: 1) 
a lower incidence of large mask leaks, 2) less frequent airway obstruction, 3) more rapid and 
frequent evaluation and adjustment of mask hold and position, 4) faster recognition of 
spontaneous breathing, 5) faster recognition of potentially injurious tidal volumes, and 6) more 
prompt and appropriate adjustment of applied airway pressures. All these effects we speculate 
will contribute to a more adequate and less injurious delivery of PPV (proportion of tidal 
volumes within the target range of safe tidal ventilation) and therefore potentially better 
resuscitation and outcome for the infants. 
2.1 
Primary Objective 
 
To test the hypothesis that observing the data and waveforms displayed on an RFM during the 
provision of PPV to preterm infants (24-27 6/7 weeks gestation) after birth will increase the 
proportion of inflations performed with a predefined VTe “safe range” of 4 – 8 mls/kg. 
2.2 
Secondary Objectives 
 
To determine whether observing the data and waveforms displayed on an RFM impact other 
longitudinal clinical, physiological, and biochemical indicators of ineffective lung aeration.   
3. Investigational Plan  
3.1 
General Design 
 
This is a multi-center, non-blinded, randomized controlled trial to evaluate whether a visible 
RFM display increases the proportion of inflations performed with VTe within target range of 4-
8 mls/kg in infants born between 24 and 27 6/7 weeks gestation receiving PPV for resuscitation 
after birth.  
 

 
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The New Life Box RFM will be used to record the parameters of all inflations delivered during 
resuscitation of all enrolled infants.  In the RFM-visible group, the information on the RFM 
display will be visible to clinical providers, while in the RFM-masked group, the RFM display will 
be masked. 
3.2 
Screening Phase 
 
The study PI and research coordinator will evaluate maternal admissions to the Labor and 
Delivery Unit at the Hospital of the University of Pennsylvania (HUP) to preliminarily assess 
eligibility based on estimated gestational age and maternal labor status.  Women with 
threatened delivery between 24-276/7 weeks gestation will be screened for eligibility. Following 
the prenatal consult performed by the clinical neonatology team, a member of the study team 
will approach the mother to offer study participation for the infant and obtain antenatal 
informed consent (See Ethics, below).  This conversation will be coordinated with other ongoing 
studies of preterm infants (See, Concurrent Enrollment). 
3.3 
Study Intervention Phase 
 
At time of resuscitation, following birth and randomization, a neonatal Respiratory Monitor 
(RFM) will be used to measure, calculate and display inflation pressures, flow and tidal volumes. 
It is standard practice in the HUP NICU to record resuscitations with the RFM masked as part of 
an ongoing departmental Quality Improvement project. 
In infants randomized to the intervention, the clinical team will be able to directly observe the 
monitor. Those randomized to the RFM-masked display arm will only see a black screen, though 
the RFM will be collecting data in the background.  
 
Oxygenation and heart rate will be measured with the Philips Intelliview vitals monitor via a 
pulse oximeter and electrocardiogram monitoring.  A pulse oximetry probe will be placed on 
each infant’s right upper extremity. The concentration of inspired oxygen (FiO2) will be 
measured with a Teledyne oxygen analyzer inserted into the inspiratory limb of the Neopuff 
circuit. In centers where it is allowed, a digital video recording of each resuscitation will be 
made. The video recording will only show the infant and the hands of staff. It will not show the 
mother, father, obstetrical staff, or obstetric procedures.  
 
All signals measured will be digitized and recorded at 200Hz using the Bicore physiological 
recording program (a customized neonatal respiratory physiology program) or Spectra 
physiological recording program (a customized neonatal respiratory physiology program).  
3.3.1 
 Allocation to Interventional Group 
 
Eligible infants born between 24 and 276/7 weeks gestation will be randomized to either have 
the RFM visible or covered.  Randomization will occur directly before delivery, so the RFM 
display can be visible or masked, according to group allocation.  Allocation will be stratified by 

 
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center and gestational age (24-25 and 26-27 weeks) using variable block (4-8) sizes. Generation 
of the randomization envelopes will be done centrally for the trial. Concealment of the 
allocation will be ensured by using opaque sealed envelopes.  
 
In case of multiple births: if two monitors are available each infant will be randomized 
separately. If only 1 monitor is available and time does not allow using the monitor for both, 
only the first born will be randomized. If time allows to use the monitor for the first and the 
following one, both/all infants will be randomized.  
 
Envelopes for each gestational age strata will be stored and available in the infant resuscitation 
room. The envelope will be opened before birth of the infant by the Neonatal Fellow or 
Neonatal Attending in charge of the resuscitation, or a member of the study team. 
3.4 
Primary Endpoint 
 
The primary endpoint is the proportion of PPV inflations with VTe between 4-8mL/kg. 
3.5 
Secondary Endpoints 
 
The secondary endpoints include the following:  
 
RFM Outcomes: 
 
 
Oximetry data on SpO2 and heart rate in the first 10 minutes from birth.  
 
Duration of significant mask leak (defined as > 60 %) as a proportion of time face mask was 
used for PPV.  
 
Significant airway obstruction (defined as a reduction in flow and volume (< 25th percentile 
of measured VTe with minimal leak during the inflation and typical flattening of the flow 
waves and the PIP was unchanged) as a proportion of the time face mask is used for PPV.  
 
Occurrence of inadequate tidal volume (defined as <4 ml/kg) as a proportion of PPV is 
given (face mask and intubated).  
 
Oxygen saturation (SpO2) levels between 3 and 10 minutes. 
 
FiO2 changes in the first 10 minutes.  
 
Total amount of pure oxygen given to the patient (oxygen load) in first 10 minutes will be 
calculated taking into consideration birth weight, tidal volume, respiratory rate, FiO2 and 
timing of stabilization.  
 
Clinical Outcomes: 
 
 
Rates of endotracheal intubation in the first 24 hours after birth. 
 
The need for circulatory support over first 24 hours (inotropes and fluid boluses). 

 
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 
Incidence of air leak (pneumothorax, pulmonary interstitial emphysema, or 
pneumomediastinum) in the first 72 hours, reported by a radiologist masked to the 
intervention.  
 
Incidence of abnormal cranial ultrasound findings (i) all intraventricular hemorrhage, (ii) 
severe – ie. Papile grade III and IV intraventricular hemorrhage, (iii) cystic periventricular 
leukomalacia before discharge from hospital. 
 
Duration of endotracheal (ET) ventilation (hours) before discharge from hospital. 
 
Duration of nasal CPAP (hours) before discharge from hospital. 
 
Duration of supplemental oxygen therapy (hours) before discharge from hospital. 
 
Total duration of assisted ventilation (ET, CPAP) in hours before discharge from hospital. 
 
Incidence of bronchopulmonary dysplasia (BPD) at 36 weeks corrected gestational age 
defined as the need for supplementary oxygen and/or any form respiratory support. The 
severity of BPD will be assessed as proposed by Jobe et al.32 and oxygen reduction test will 
be performed in case of moderate BPD as described by Walsh et al. 33  
 
Neonatal mortality – death in the DR, within a week after birth, before discharge from 
hospital. 
 
Composite outcome of death or BPD. 
 
Retinopathy of prematurity needing treatment.  
 
Necrotizing enterocolitis grade 2 or more.  
 
4. Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
 Gestational age (GA) 24 – 27 6/7  weeks at birth, by best obstetrical estimate 
 Receive positive pressure ventilation during delivery room resuscitation 
4.2 
Exclusion Criteria 
 Known major anomalies including that may affect measured cardiorespiratory 
parameters: congenital diaphragmatic hernia, trachea-oesophageal fistula, cyanotic 
heart disease, pulmonary hypoplasia  
 RFM not available during resuscitation. 
4.3 
Subject Recruitment 
 
Parents of potentially eligible infants will be approached on an inpatient basis, once admitted 
to the Labor and Delivery service at HUP.  The study team will be made aware of potential 
parents through communication with the inpatient clinical neonatology team, who perform 
clinical consults on all admitted pregnant women with threatened preterm delivery. 
4.4 
Duration of Participation 
 

 
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The intervention will involve monitoring the infant in the resuscitation room following delivery 
until determined by the clinical team as stable or for the first 15 minutes of resuscitation. The 
remaining information for this study will be extracted from the participant medical record.  
There is no follow up involvement after hospital discharge. 
4.5 
Total Number of Subjects and Sites 
 
There are 6 clinical sites.  Recruitment will end when approximately 286 evaluable infants are 
recruited.  At UPenn, we anticipate enrolling 80 infants over 3 years in order to produce 50 
evaluable subjects. 
 
The 6 sites include: 
1. Hospital of the University of Pennsylvania, Philadelphia, United States 
2. Leiden University Medical Center, Leiden, the Netherlands  
3. Department of Newborn Research, Royal Women’s Hospital, Melbourne, Australia  
4. Maternal & Children’s University Hospital La Fe, Valencia, Spain  
5. Neonatal Intensive Care Unit, V.Buzzi Children's Hospital, Milan, Italy 
6. Karolinska University Hospital Huddinge, Stockholm, Sweden  
 
Infant’s transferred from HUP to Children’s Hospital of Philadelphia (CHOP) for continued 
medical care before 36 weeks corrected gestational age will have their medical records 
reviewed for long term outcome data. 
4.6 
Vulnerable Populations:  
 
This study will enroll neonates, in accordance with HHS regulations 45CFR 46. 
5. Study Intervention 
5.1 
Description 
 
All enrolled infants will have RFM recording performed during delivery room resuscitation.  For 
infants in the RFM-visible group, the RFM display will be visible.  For infants in the RFM-masked 
group, the RFM display will not be visible. 
5.2 
Subject Encounter: Delivery Room 
 
There is only one subject encounter in this study design: the respiratory function monitoring 
performed during delivery room stabilization.  Data collected to ascertain the secondary 
outcomes will be obtained from review of the medical record. 
 
The study PI will train the resuscitation team in the use of all equipment.  The respiratory 
therapists specifically will be responsible for ensuring the equipment is correctly set up prior to 

 
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use.  The RFM (NewLife Box, Advanced Life Diagnostics) will be calibrated and set up prior to 
delivery.  A disposable neonatal flow transducer (Avea neonatal flow sensor, Carefusion, Yorba 
Linda CA) will be placed in line between the facemask and respiratory device. Resuscitation 
team members will follow a standard protocol to set up the RFM and initiate recording, which 
does not require technical expertise.   Data files will be labeled with a unique study-specific 
identifier that does not contain protected information.  The monitor itself is user-friendly, and 
requires only pressing a button to initiate recording. 
 
The RFM has a button that will cause the screen to be black, although the monitor is still 
recording respiratory function data. Once the randomization envelope is opened, the screen 
will be either left visible or “blacked out” according to the assigned group allocation. 
5.3 
Training 
 
Training and increasing experience in RFM may lead to greater benefits.29,31 To ensure all 
resuscitators will use a RFM with confidence, adequate training of all personnel involved must 
precede the trial. The training will take place in each participating center, led by the experts in 
delivery room recording and use of the RFM monitor.  
At HUP, all neonatal providers who perform the “leader” role during infant resuscitation will 
receive standardized training in RFM waveform and output interpretation.  
5.4 
Blinding 
 
It is impossible to blind the caregivers to the intervention as the display will be clearly either 
visible or masked. However, we plan to centralize waveform, data and video analysis from the 
monitor whereby the individual (PhD student in Leiden) is blinded to the allocation. 
5.5 
Technique of Resuscitation 
 
Other than allocation of the visible or masked RFM, all other resuscitative measures (e.g. 
intubation, external cardiac massage, administration of oxygen and other drugs) will be at the 
discretion of the staff involved, following local standard of care protocols. 
 
The primary equipment used to provide resuscitation will be a T-piece device.  
 
When performing a delivery room trial in multiple centers, different local resuscitation 
guidelines are inevitable. However, this can be considered as strength of the trial as this could 
show that using a monitor is useful independent of practiced resuscitation guidelines. 
 
5.6 
Discontinuation of Monitoring 
 
The sensors will be removed from the circuit at the following events, whichever occurs first: 

 
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 The infant is stabilized on non-invasive support and is transitioned to nasal prong CPAP 
 Disconnection of the endotracheal tube for administration of surfactant delivery or 
connection to the ventilator 
 15 minutes of recording have elapsed 
 At the discretion of the resuscitation team leader 
 
After the sensors are removed from the circuit, the New Life Box will recording will be 
discontinued.  The program will automatically save the data file under the study-specific 
identifier that was entered during the set-up process. 
6. Study Procedures 
All encounters will take place during the hospitalization.  Screening will occur on an antenatal 
basis, and the study encounter will take place during delivery room resuscitation after birth.  All 
subsequent data will be collected from the patient medical record.  
6.1 
Screening 
 
Screening will take place on an antenatal basis.  Women admitted to the Labor and Delivery 
floor with threatened preterm delivery between 24-27 6/7 weeks will be screened for eligibility.  
Parents of potentially eligible infants will be approached to offer study participation and obtain 
informed consent. 
6.2 
Study Intervention Phase 
 
As noted in Section 5.2, the only study-related intervention is use of the RFM (either blinded or 
visible) during delivery room resuscitation. 
6.3 
Data Collection Phase 
 
Secondary outcomes will be collected from the clinical medical record. In the case the infant is 
transferred to CHOP for care before 36 weeks corrected gestational age, the CHOP medical 
record will be reviewed for long term data. 
 
6.4 
Subject 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 due to changes in 
clinical status that make them ineligible for the study (ie, congenital anomaly diagnosed, or PPV 
not given during resuscitation).  The Investigator may also withdraw subjects after enrollment if 
data is found to be incomplete or poor quality after the delivery room encounter.  
 

 
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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. 
 
Statistics on the number of subjects who are withdrawn and the reason for withdrawal will be 
maintained to account for all enrolled subjects. 
6.5 
Safety Evaluations 
 
In accordance with University of Pennsylvania Research Policies and Procedures, Federal and 
State Laws and Regulations, and section 10, subsection 1, of the Dutch WMO, the investigator 
will inform the subjects’ parents or caregivers and the reviewing accredited IRB if anything 
occurs, on the basis of which it appears that the disadvantages of participation may be 
significantly greater than was foreseen in the research proposal. The study will be suspended 
pending further review by the accredited IRB, except insofar as suspension would jeopardize 
the subjects’ health. The investigator will ensure that all subjects’ parents or caregivers are kept 
informed. 
7. Statistical Plan 
7.1 
Baseline Data 
 
Baseline and demographic characteristics will be summarized by standard descriptive statistics 
(including mean and standard deviation for continuous variables, such as birth weight and 
standard percentages for dichotomous variables such as sex) 
7.2 
Primary and Secondary Outcomes 
 
The Primary outcome will be analyzed as a comparison of proportion of tidal volumes within 
the predefined safe range (4-8 mls/kg) between the RFM exposed and RFM masked groups 
using Chi square test.  
 
Secondary outcome measures of ineffective lung aeration will be analyzed through mean and 
proportion comparisons between the RFM exposed and RFM masked groups. 
7.3 
Sample Size and Power Determination 
 
There are few data available to estimate possible improvements when a RFM is used. Only one 
small feasibility study (from Melbourne, one of the participating centers) is available where 
median mask leak decreased from 54 (37-82) % to 37 (21-54) % when a monitor was used, PIP 
was adjusted more often (42 % vs 9%), mask was repositioned more often (73 vs 26%) and less 
infants had Vte > 8 mL/kg (20% reduction). It is likely that less mask leak and pressure 
adjustment led to more efficient respiratory support and this explains why less infants < 32 

 
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weeks of gestation needed intubation in the delivery room in the group where the RFM was 
visible (21 % vs 57 %; p = 0.035).31 In addition, Wood et al, showed, in a manikin study, that 
mask leak was halved when a RFM was used during mask ventilation. 23  
 
The primary outcome will be the proportion of tidal volumes within the target range (4 - 8 
ml/kg).  This will be calculated as the proportion of adequate tidal volume of the total amount 
of inflations per infant. The duration of PPV provided will vary between infants and this may be 
a source of bias. To minimize this, we will take the proportion of adequate tidal volume as a 
percentage of the total amount of inflations per infant.  
 
About 60 infants <28 weeks of gestation are born a year in each neonatal center. Almost all 
infants receive PPV at birth. Currently the median (IQR) proportion of adequate tidal volumes 
given to infants during PPV at birth is 25% (5%-45%) (based on recordings in Leiden). Therefore, 
we calculated to detect an 40% absolute increase in proportion of adequate tidal volumes 
(corresponding to an increase from 25% to 35%) with a power of 80% and an α error of 5% (two 
tailed test), 143 infants are required for each arm.  
 
With 6 centers participating and on average 50 infants < 28 weeks gestation per year per center 
and taking into account (based on previous delivery room trials using waiver of consent) an 
estimated 20% of denials for consent, missed eligible patients, problems with equipment, we 
will be able to recruit 286 infants in 18-36 months. We expect that the data entry, analysis and 
writing of the manuscript will take another 6-12 months.  
 
The incidence of intubation is not an appropriate outcome for calculating sample power in this 
trial because the decision is often based on local protocols rather than clinical need. The need 
for intubation in the group blinded to the RFM in the Schmoelzer study was unusually high in 
that small trial and does not reflect the experience in other centers who may have a higher 
threshold for intubation. In addition, it will be difficult to reach consensus between the 
participating centers as different intubation criteria are currently used. 
8. Safety and Adverse Events 
8.1 
Definitions 
8.1.1 Adverse Event 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  All adverse events observed by the investigator or his staff will be recorded. 
8.1.2 Serious Adverse Event 
 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  

 
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 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events. 
8.2 
Recording of Adverse Events 
 
Adverse events and their relationship to study, severity, time of experience, expectation, 
actions taken to resolve the event and final outcome will be recorded as documented in the 
medical record, or if reported by the NICU team even before documentation.    
Information on all adverse events will be recorded immediately in the source document, and 
also in the appropriate adverse event module of the case report form (CRF).  
 
All adverse events occurring in the infant resuscitation room will be recorded. The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study participation is not the cause 
8.3 
Relationship of AE to Study 
 
The extremely preterm subjects in this study will each experience expected and unexpected 
adverse events. Many extremely preterm infants experience serious adverse events, such as 
death or life-threatening events, based on their underlying prematurity.   
 
However, because of the high acuity of subjects during delivery room stabilization, adverse 
events will be monitored during the study to ensure timely detection of events that may affect 
safety.  Specifically, all adverse events (serious or non-serious) that occur in the delivery room 
setting will be assessed and recorded.  The local study investigator will determine the 
relationship between study procedure and adverse events that occur in the delivery room 
(definitely related, probably related, possibly related, unlikely or unrelated). 
 
Of note: because need for positive pressure after birth is an inclusion criteria for this study, 
respiratory failure requiring PPV or endotracheal intubation after birth will not be considered 
an adverse event.    
 
Events that occur once the baby is transferred to the NICU are unlikely to have resulted from 
the use of the RFM during delivery room stabilization.  Adverse outcomes related to extreme 
prematurity may occur during the NICU hospital stay and are pre-defined secondary outcomes 
in this study (see Secondary Endpoints, Section 3.2.2).  These outcomes will not be reported on 

 
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an individual basis, but they will be analyzed by the DSMB every 6 months to assess whether 
there are significant imbalances between study groups with regards to these outcomes. 
 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
 
Investigators will submit reports of the following problems within 24 hours from the time the 
investigator becomes aware of the event: Any serious adverse event that occurs any time 
during or after the research study, which in the opinion of the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information) AND Related to the research procedures (An event is 
“related to the research procedures” if in the opinion of the principal investigator or sponsor, 
the event was more likely than not to be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to 
the Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others 
Including Reportable Adverse Events” or as a written report of the event (including a 
description of the event with information regarding its fulfillment of the above criteria, follow-
up/resolution and need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file as well as forwarded to the Coordinating site in Leiden.  
 
8.4.1 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 will be submitted to the IRB. 
8.4.2 Investigator Reporting: Notifying the Penn IRB 
 
The UPenn site PI will report all reportable adverse events to the Penn IRB in accordance with 
the Penn IRB definition of reportable events and reporting timelines.  Documentation of all 
reported events and any associated decisions made by the IRB will be forwarded to the lead 
clinical site and coordinating PI in Leiden. 
Investigators at other sites will be responsible for safety reporting to their local IRBs.  
 
8.5 
Data and Safety Monitoring Plan 
 

 
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The trial has an external Data Safety and Monitoring Board, chaired by Dr. Anton van Kaam.  
The DSMB charter details the frequency of DSMB meetings, specified analyses and stopping 
rules, and specific roles of the DSMB. 
 
Interim analysis September-October 2017  
 
A pre-planned interim analysis of the Monitor trial was performed after 50% of inclusions with 
primary outcome data were available. The investigator and the statistician involved in the trial 
collected and performed the analysis blinded for the groups. The results were submitted to the 
DSMB on the 25th of October 2017. The results showed no safety concerns, but also no 
difference in primary outcome (proportion of tidal volume delivered between 4-8 mL/kg) with a 
p value of 0.96. Since this met the criterion of the pre-defined stopping rule in futility (p-value > 
0.90), the DSMB recommended to stop the trial on November 14, 2017.  
 
The recommendation was immediately communicated with all principal investigators of the 
sites participating in the trial and the recruitment was temporarily halted. A Steering 
Committee conference call was held to discuss the recommendation on November 28, 2017. All 
investigators agreed to continue the trial and reach full recruitment, based on the following:  
 At the time the recommendation of the DSMB became available, the recruitment rate 
was already at 75%. Collecting the data for the primary outcome was a time-consuming 
process as the analysis of the respiratory function needed to be performed manually. 
 The presence of a learning curve in using the monitor was proposed and continuing 
recruitment will increase the chance of observing chances in performance as centers 
gain experience. 
 There is no evidence of safety concerns 
  
Given this, all members of the Steering Committee agreed continue enrollment to reach the 
original goal enrollment, anticipated by the end of 2018.  
 
This decision was endorsed by the DSMB.   
 
9. Study Administration, Data Handling, and Record Keeping 
9.1 
Confidentiality 
 
All research team members at UPenn are CITI Human Subject Protection and Good Clinical 
Practice certified, as a requirement of their participation in any study.  The basic rights of study 
participants will be respected and maintained by the investigators and by all who are involved 
in the collection or processing of individually identified data. All data collection and processing 
procedures are designed to protect individual rights and to comply with all applicable laws and 
ethical principles including confidentiality. Among the rights that must be protected are:  

 
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 the right to informed consent, which requires that prospective participants in a research 
project and, if needed, their family members, be provided adequate information about 
the potential risks, benefits, and requirements of participation so that each can make an 
informed decision about participation 
 the right to decline, which requires that prospective participants be fully informed that 
their participation is completely voluntary, that they may withdraw at any time, that 
access to adequate health care will be provided whether or not they participate in the 
research, and that they may refuse to answer any question  
 the right to privacy, which requires guarantees of confidentiality of information and 
other specific protection as specified in the Privacy Act of 1974. 
The basic rights of study participants will be respected and maintained by the investigators and 
by all who are involved in the collection or processing of individually identified data. Our data 
collection and processing procedures are designed to protect individual rights and to comply 
with all applicable laws and ethical principles.  
 
The data collection forms will include unique study ID numbers only and basic demographic 
data as participant identifiers. Thus, the files maintained will contain limited identifying 
information and protect subject confidentiality. Safeguards are in place to greatly decrease the 
chances that characteristics of a case can be linked to the individual participating in the study.  
Access to direct identifiers will be limited to staff who meet all relevant training requirements 
and are assigned to (or support) this project, and who must have access to these identifiers for 
purposes of quality control and monitoring. All other persons, including statisticians and 
investigators will be blinded to identifiers until such time as for reasons of safety or clinical 
care, those identifiers must be shared. All data with identifiers will be stored on firewall-
protected secure servers. 
9.2 
Data and Device Collection, Storage, and Management 
9.2.1 Storage of the RFM 
The RFM is locked and secured in the restricted-access infant resuscitation room (IR). The RFM 
is clearly labeled for ‘RESEARCH USE ONLY’ and contact information for the PI and study team 
are provided. The RFM is routinely checked by clinical engineering and ongoing updates and 
software checks are performed by the study team and the developers in Leiden, Netherlands.  
9.2.2 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 

 
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subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
 
9.2.3 Video Recordings 
 
Video recordings are standardly made during newborn resuscitations for quality improvement 
and audit, educational, and research purposes. Video recordings are used as quality assurance 
during the data processing for the RFM. The video recordings are used and viewed by the 
Neonatology Department for QI purposes, and according to hospital policy, must be deleted 
after 30 days unless a release is provided. In this study, video files provide a method to clearly 
identify actions such as mask repositioning or spontaneous breathing, and they improve 
interpretation of respiratory waveforms under these conditions. Parents of enrolled 
participants will be provided the option to give their permission for the use of the video 
recording of their infant’s resuscitation for research purposes. If permission is obtained, the 
videos will be labeled with the study identifier and the video recordings will be securely 
transferred onto the computer of the PI. They will be maintained on a password protected 
computer on the secure HUP server in a locked office. Following 30 days, only study staff at 
HUP and at Leiden will have the ability to access and view the video recordings. The videos will 
be securely transferred with the RFM files to the coordinating site in Leiden through a secure 
file transfer protocol. Once all the RFM data records have been reviewed and analyzed, the 
video recordings will be deleted.  
 
9.2.4 
Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For clarification 
of illegible or uncertain entries, print the clarification above the item, then initial and date it. 
Each study subject will be assigned a unique study identifier.  The study coordinator will keep a 
master list that links the identifiable information (MRN) with the study identifier.  All case 
report forms will only contain the unique study ID.  
 
The master list will be securely stored on a password protected file on a secure server in the 
locked office of the study coordinator.  
9.2.5 Data Management 
 

 
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Data concerning eligibility, randomization, basic characteristics, delivery room management, 
parameters from the recordings and outcome parameters will be collected according to the CRF 
forms. The coordinating site will use a secured web based database (proMISe) to manage the 
collaborative data. 
 
When infants are eligible, but not randomized or excluded afterwards, only the screening CRF 
concerning eligibility and randomization will be completed.    
 
Individual patient RFM data will be stored on a secure server on a password protected 
computer accessible to the HUP study team.  The data will be centrally managed at the 
University of Leiden.  At regular intervals the collected RFM data, with identifiers removed, will 
be securely sent to the PhD candidate in Leiden for analysis. The analysis will be supervised by 
Arjan te Pas. Support for data management and statistical analysis will be provided by the study 
statistician.  
9.3 
Records Retention 
 
The study team will retain study essential documents for at least 3 years after publication of 
study findings. 
10. Ethical Considerations 
 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies 
and procedures. 
10.1 Risks 
 
This is a minimal risk study. It is standard practice in the HUP NICU to record infant data with 
the RFM masked for all infants less than 32 weeks with the RFM monitor. This is part of a 
department quality improvement initiative (IRB reviewed INTRO QI initiative).  
 
The Avea neonatal flow sensors (Carefusion) added in line are FDA-approved for clinical use.  
The potential risks include minimal added dead space to the respiratory circuit with the sensors 
in place (approximately 0.7mL of dead space).  This is not considered to be a significant addition 
to potential dead space in the circuit, after considering the existing respiratory tubing and 
facemask. Previous published studies of RFM have not reported adverse events due to the 
sensors’ presence. 
 
All other physiologic monitoring will be obtained using the current standard-of-care sensors (ie, 
heart rate, respiratory rate, and pulse oximetry).  Data from all of these sensors will be 
collected and recorded by the New Life Box Respiratory Function Monitor.  The New Life Box is 

 
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a research tool with FCC conformity that integrates and records data streaming from multiple 
data sources.   
 
We do not yet know the optimal information that should be presented to clinicians to improve 
clinical care and therefore there is the potential that viewing the RFM could alter the care of 
the clinical team within the scope of standard care practices.  Previous studies of RFM use in 
the clinical environment have not described adverse effects on the resuscitation team’s 
performance from using the RFM.  However, the resuscitation team leader can turn off the RFM 
display at any point during the resuscitation if s/he is concerned about the impact of the RFM 
on the resuscitation (See Section 5.6, Discontinuation of Monitoring).  
 
Investigational devices that carry significant risk must have an investigational device exemption 
(IDE) filed prior to initiation of clinical studies. Research involving non-significant risk devices is 
subject to approval by appropriate IRBs but does not require an IDE prior to initiation of the 
research. Because the NewLifeBox is a non-significant risk device, we will not seek an IDE, based 
on The Federal Drug Administration Code of Federal Regulations: CFR Title 21, Section 812.3.  
10.2 Risk Benefit Assessment 
 
Potential direct benefits to the subjects with the RFM screen visible include the potential for 
higher proportion of PPV inflations delivered within a pre-specified “safe” VTe range. The 
indirect benefit of study participation is the contributing to the scientific knowledge for future 
preterm infants.  The study outlined in this proposal will generate important knowledge about 
the respiratory characteristics associated with lung aeration in extremely preterm infants.  
Given that the risks of the study are minimal and the potential benefits to future infants, it is 
reasonable to proceed with the project. 
10.3 Informed Consent Process / HIPAA Authorization 
 
Prior to delivery, the PI or study coordinator will obtain antenatal consent and HIPAA 
authorization from the parents of potentially eligible infants. The consent process will take 
place in a private room. Following the consent discussion, a copy of the consent form will be 
provided to the parents, and they will have the opportunity to review the form before providing 
consent.  
10.3.1 Co-Enrollment 
 
There is potential for co-enrollment with other delivery room studies that require antenatal 
consent.  The Monitor study team will communicate with other neonatal study teams to ensure 
that consent discussions are coordinated among all investigators, in order to reduce the 
parental burden. 
 

 
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Co-enrollment with other interventional trials, including Neonatal Network trials, will be 
reviewed and approved by the appropriate concurrent research committees and Monitor trial 
coordinating PI. 
 
Of note, this study will co-enroll some infants who are enrolled in the ongoing SAIL (Sustained 
Aeration of Infant Lungs) trial.  The SAIL trial Executive committee has approved co-enrollment 
for the SAIL and Monitor trials.  
 
10.4 Waiver of assent 
 
As the subjects are infants, assent will not be obtained. 
10.5 Funding Source 
 
There is no external funding source or study sponsor.  Dr. Foglia currently has 75% of her time 
protected for research, has already obtained the RFM that will be used for this study, and has 
grant funds to cover the cost of RFM sensors and equipment.  Thus, there are sufficient 
resources to start this study.  
10.6 Conflict of Interest 
 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research.  
10.7 Subject Payments 
 
No payments or gifts will be made to families or subjects for participation in this study. 
10.8 Publication Plan 
 
Research results will be made available to the scientific community and public in a timely 
manner. The primary method by which data are shared with the scientific community is 
through peer-reviewed publications and presentation at meetings.  
11. References 
1. te Pas AB, Walther FJ. Ventilation of very preterm infants in the delivery room. Current 
Pediatric Reviews. 2006; 2:187-197.  
2. te Pas AB, Davis PG, Hooper SB, Morley CJ. From liquid to air: breathing after birth. J Pediatr. 
2008;152:607-611.  
3. Euro-Peristat project. European Perinatal Health Report. 2008.  

 
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4. Wada K, Jobe AH, Ikegami M. Tidal volume effects on surfactant treatment responses with 
the initiation of ventilation in preterm lambs. J Appl Physiol. 1997;83:1054-1061.  
5. te Pas AB, Walther FJ. A randomized, controlled trial of delivery-room respiratory 
management in very preterm infants. Pediatrics. 2007;120:322-329.  
6. Bjorklund LJ, Ingimarsson J, Curstedt T, John J, Robertson B, Werner O, et al. Manual 
ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent 
surfactant replacement in immature lambs. Pediatr Res. 1997;42:348-355. 
7. Bjorklund LJ, Ingimarsson J, Curstedt T, Larsson A, Robertson B, Werner O. Lung recruitment 
at birth does not improve lung function in immature lambs receiving surfactant. Acta 
Anaesthesiol Scand. 2001;45:986-993.  
8. Ingimarsson J, Bjorklund LJ, Curstedt T, Gudmundsson S, Larsson A, Robertson B, et al. 
Incomplete protection by prophylactic surfactant against the adverse effects of large lung 
inflations at birth in immature lambs. Intensive Care Med. 2004;30:1446-1453.  
9. Ikegami M, Kallapur S, Michna J, Jobe AH. Lung injury and surfactant metabolism after 
hyperventilation of premature lambs. Pediatr Res. 2000;47:398-404.  
10. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M. Decreased indicators of lung injury 
with continuous positive expiratory pressure in preterm lambs. Pediatr Res. 2002;52:387-392.  
11. Jobe AH. Transition/adaptation in the delivery room and less RDS: "Don't just do something, 
stand there!". J Pediatr. 2005;147:284-286.  
12. Jobe AH, Ikegami M. Mechanisms initiating lung injury in the preterm. Early Hum Dev. 
1998;53:81-94.  
13. Aly H, Massaro AN, Patel K, El Mohandes AA. Is it safer to intubate premature infants in the 
delivery room? Pediatrics. 2005;115:1660-1665.  
14. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at 
birth for very preterm infants. N Engl J Med. 2008;358:700-708.  
15. Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J, et al. Neonatal 
resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation 
and Emergency Cardiovascular Care. Pediatrics. 2010;126:e1400-e1413.  
16. O'donnell CP, Davis PG, Morley CJ. Positive pressure ventilation at neonatal resuscitation: 
review of equipment and international survey of practice. Acta Paediatr. 2004;93:583-588.  
17. Kattwinkel J. Textbook of neonatal resuscitation. 4th ed. ed. American Academy of 
Pediatrics and American Heart Association; 2000.  

 
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18. Wood FE, Morley CJ, Dawson JA, Kamlin CO, Owen LS, Donath S, et al. Improved techniques 
reduce face mask leak during simulated neonatal resuscitation: study 2. Arch Dis Child Fetal 
Neonatal Ed. 2008;93:F230-F234.  
19. Finer NN, Rich W, Wang C, Leone T. Airway obstruction during mask ventilation of very low 
birth weight infants during neonatal resuscitation. Pediatrics. 2009;123:865-869.  
20. Klimek J, Morley CJ, Lau R, Davis PG. Does measuring respiratory function improve neonatal 
ventilation? J Paediatr Child Health. 2006;42:140-142.  
21. South M, Morley CJ. Monitoring spontaneous respiration in the ventilated neonate. Arch Dis 
Child. 1986;61:291-294.  
22. Keszler M. Volume-targeted ventilation. J Perinatol. 2005;25 Suppl 2:S19-S22.  
23. Wood FE, Morley CJ, Dawson JA, Davis PG. A respiratory function monitor improves mask 
ventilation. Arch Dis Child Fetal Neonatal Ed. 2008;93:F380-F381. 
24. Schilleman K, Witlox RS, Lopriore E, Morley CJ, Walther FJ, te Pas AB. Leak and obstruction 
with mask ventilation during simulated neonatal resuscitation. Arch Dis Child Fetal Neonatal Ed. 
2010;95:F398-F402.  
25. Vento M, Saugstad OD. Oxygen as a therapeutic agent in neonatology: a comprehensive 
approach. Semin Fetal Neonatal Med. 2010;15:185.  
26. The International Liaison Committee on Resuscitation (ILCOR) consensus on science with 
treatment recommendations for pediatric and neonatal patients: neonatal resuscitation. 
Pediatrics. 2006;117:e978-e988.  
27. Schmolzer GM, Kamlin OF, Dawson JA, te Pas AB, Davis PG, Morley CJ. Respiratory 
monitoring of neonatal resuscitation. Arch Dis Child Fetal Neonatal Ed. 2009.  
28. Kattwinkel J, Stewart C, Walsh B, Gurka M, Paget-Brown A. Responding to compliance 
changes in a lung model during manual ventilation: perhaps volume, rather than pressure, 
should be displayed. Pediatrics. 2009;123:e465-e470.  
29. Schilleman K, Siew ML, Lopriore E, Morley CJ, Walther FJ, te Pas AB. Auditing resuscitation 
of preterm infants at birth by recording video and physiological parameters. Resuscitation. 
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