Delayed Cord Clamping for Intubation and Gentle Ventilation in Infants With Congenital Diaphragmatic Hernia
Phase: NA
Conditions: Congenital Diaphragmatic Hernia
Sponsor: Children's Hospital of Philadelphia

DING Protocol 
PI: Foglia 
 
 
 
Title: 
Delayed Cord Clamping for Intubation and Gentle 
Ventilation in Infants with Congenital Diaphragmatic 
Hernia: A Pilot Feasibility Trial 
Short Title 
Delayed Cord Clamping for CDH Pilot Trial  
Drug or Device 
Name(s): 
N/A 
Regulatory Sponsor: 
N/A 
eIRB Number 
17-014125 
NCT Number 
NCT03314233 
Protocol Date: 
September 5, 2018 
Amendment 1 Date: January 3, 2018 
Amendment 3 Date: April 11, 2018 
Amendment 2 Date: February 2, 2018 
Amendment 4 Date: June 19, 2018 
Amendment 5 Date: September 5, 2018 
 
 
 
Principal Investigator:  
Elizabeth Foglia, MD MSCE 
The Children’s Hospital of Philadelphia 
34th and Civic Center Blvd 
2nd Floor Main Building 
Neonatology Office Suite 
Philadelphia, PA, 19104 
Phone 215-590-1653 
email: foglia@chop.edu 
 
Co-Investigators: 
David Munson, MD 
Natalie Rintoul, MD 
Anne Ades, MD 
Holly Hedrick, MD 
Juliana Gebb, MD 
Julie Moldenhauer, MD 
Joanna Cole, PhD  
 
 

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TABLE OF CONTENTS 
Table of Contents.................................................................................................... ii 
Abbreviations and Definitions of Terms .............................................................. iv 
Abstract ................................................................................................................... v 
Protocol Synopsis ................................................................................................ vii 
1 
BACKGROUND INFORMATION AND RATIONALE .................................................................... 1 
1.1 INTRODUCTION ........................................................................................................................... 1 
1.2 NAME AND DESCRIPTION OF INVESTIGATIONAL INTERVENTION: ..................................................... 1 
1.3 RELEVANT LITERATURE AND DATA ............................................................................................... 2 
1.3.1 
Delayed Cord Clamping .................................................................................................... 2 
1.3.2 
Animal models .................................................................................................................. 3 
1.3.3 
Clinical trials in preterm infants ......................................................................................... 3 
1.4 COMPLIANCE STATEMENT ........................................................................................................... 5 
2 
STUDY OBJECTIVES .................................................................................................................... 5 
2.1 PRIMARY AIM .............................................................................................................................. 5 
2.2 SECONDARY AIM ........................................................................................................................ 5 
3 
INVESTIGATIONAL PLAN ............................................................................................................. 5 
3.1 GENERAL SCHEMA OF STUDY DESIGN ......................................................................................... 5 
3.1.1 
Screening Phase ............................................................................................................... 5 
3.1.2 
Study Treatment Phase (start of the study intervention) .................................................. 6 
3.1.3 
Follow-up Phase ............................................................................................................... 6 
3.2 ALLOCATION TO TREATMENT GROUPS AND BLINDING ................................................................... 6 
3.3 STUDY DURATION, ENROLLMENT AND NUMBER OF SITES.............................................................. 6 
3.3.1 
Duration of Study Participation ......................................................................................... 6 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................... 6 
3.4 STUDY POPULATION ................................................................................................................... 6 
3.4.1 
Inclusion Criteria ............................................................................................................... 6 
3.4.2 
Exclusion Criteria .............................................................................................................. 7 
4 
STUDY PROCEDURES .................................................................................................................. 7 
4.1 SCREENING VISIT ....................................................................................................................... 7 
4.2 STUDY TREATMENT PHASE ......................................................................................................... 7 
4.2.1 
Visit 1: Delivery visit .......................................................................................................... 7 
4.3 FOLLOW-UP PHASE ..................................................................................................................... 8 
4.4 SUBJECT COMPLETION/WITHDRAWAL .......................................................................................... 8 
4.4.1 
Early Termination Study Visit ............................................................................................ 8 
5 
STUDY EVALUATIONS AND MEASUREMENTS......................................................................... 8 
5.1 IDENTIFICATION OF ELIGIBLE SUBJECTS ........................................................................................ 8 
5.2 SCREENING AND MONITORING EVALUATIONS ............................................................................... 9 
5.2.1 
Medical Record Review .................................................................................................... 9 
5.2.2 
Video Recording ............................................................................................................. 10 
5.2.3 
Laboratory Evaluations ................................................................................................... 10 
5.3 EFFICACY EVALUATIONS ........................................................................................................... 10 
5.4 SAFETY EVALUATION ................................................................................................................ 10 
6 
STATISTICAL CONSIDERATIONS ............................................................................................. 11 
6.1 PRIMARY ENDPOINT .................................................................................................................. 11 
6.2 SECONDARY ENDPOINTS ........................................................................................................... 11 

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6.3 STATISTICAL METHODS ............................................................................................................. 12 
6.3.1 
Baseline Data .................................................................................................................. 12 
6.3.2 
Primary Analysis ............................................................................................................. 12 
6.3.3 
Safety Analysis ............................................................................................................... 12 
6.4 SAMPLE SIZE AND POWER ......................................................................................................... 13 
6.5 INTERIM ANALYSIS .................................................................................................................... 13 
7 
STUDY INTERVENTION .............................................................................................................. 13 
7.1 DESCRIPTION ........................................................................................................................... 13 
8 
SAFETY MANAGEMENT ............................................................................................................. 14 
8.1 CLINICAL ADVERSE EVENTS ...................................................................................................... 14 
8.2 ADVERSE EVENT REPORTING .................................................................................................... 15 
8.3 DEFINITION OF AN ADVERSE EVENT ........................................................................................... 15 
8.4 DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) .................................................................... 15 
8.4.1 
Relationship of SAE to study drug or other intervention ................................................. 15 
8.5 IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS .................................. 16 
8.5.1 
Follow-up report .............................................................................................................. 16 
9 
STUDY ADMINISTRATION .......................................................................................................... 16 
9.1 TREATMENT ASSIGNMENT METHODS ......................................................................................... 16 
9.1.1 
Randomization ................................................................................................................ 16 
9.1.2 
Blinding ........................................................................................................................... 16 
9.2 DATA COLLECTION AND MANAGEMENT....................................................................................... 16 
9.3 CONFIDENTIALITY ..................................................................................................................... 17 
9.4 REGULATORY AND ETHICAL CONSIDERATIONS ........................................................................... 18 
9.4.1 
Data and Safety Monitoring Plan .................................................................................... 18 
9.4.2 
Risk Assessment ............................................................................................................ 18 
9.4.3 
Potential Benefits of Trial Participation ........................................................................... 20 
9.4.4 
Risk-Benefit Assessment ................................................................................................ 20 
9.5 RECRUITMENT STRATEGY ......................................................................................................... 20 
9.6 INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ........................................................ 20 
9.6.1 
Waiver of Assent ............................................................................................................. 21 
9.7 PAYMENT TO SUBJECTS/FAMILIES ............................................................................................. 21 
9.7.1 
Gifts ................................................................................................................................. 21 
10 PUBLICATION ............................................................................................................................ 21 
11 REFERENCES ............................................................................................................................ 22 
 
 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
AE 
 
Adverse event 
CDH 
CFDT 
CHOP 
 
Congenital diaphragmatic hernia 
Center for fetal diagnosis and treatment 
Children’s Hospital of Philadelphia 
DCC 
DING 
DSMB 
SAE 
SDU 
 
Delayed cord clamping 
Delayed cord clamping, Intubation, Gentle ventilation 
Data safety monitoring committee 
Serious adverse event 
Special delivery unit 
UCC 
 
Umbilical cord clamping 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABSTRACT 
Context:  Congenital diaphragmatic hernia (CDH) is a congenital anomaly 
associated with a high risk of mortality and need for life-saving interventions such as 
ECMO, nitric oxide, and vasopressor support. Although infants with CDH 
experience significant morbidity and mortality starting immediately after birth, high 
quality evidence informing delivery room resuscitation in this population is lacking. 
Infants with CDH are at risk for pulmonary hypoplasia and pulmonary hypertension 
and often experience hypoxemia and acidosis during neonatal transition.  The 
standard approach to DR resuscitation is immediate umbilical cord clamping (UCC) 
followed by intubation and mechanical ventilation.  Animal models suggest that 
achieving lung aeration prior to UCC results in improved pulmonary blood flow and 
cardiac function compared with immediate UCC before lung aeration is established. 
Trials of preterm infants demonstrated that initiating respiratory support prior to 
UCC is safe and feasible.  Because infants with CDH are at high risk for pulmonary 
hypertension and systemic hypotension, they may benefit from the hemodynamic 
effects of lung aeration before UCC, namely increased pulmonary blood flow, 
decreased pulmonary vascular resistance, and improved cardiac output.  To date, 
this approach has not been studied in infants with CDH.   
 
Objective: To establish the safety and feasibility of delaying cord clamping until 
intubation and lung aeration has been achieved in infants with CDH. 
 
Study Design: Unblinded single-arm pilot interventional trial.  All eligible enrolled 
infants will receive the DING intervention (Delayed cord clamping for INtubation and 
Gentle ventilation).  
 
Setting/Participants: This study will take place in the CHOP Special Delivery Unit 
(SDU).  
Inclusion criteria: (1) Antenatal diagnosis of CDH; (2) Gestational age ≥ 36 weeks 
Exclusion criteria: (1) Multiple gestation; (2) Other major congenital anomalies or 
aneuploidy; (3) Enrollment in FETO (Fetoscopic endoluminal tracheal occlusion) 
trial; (4) Palliative care planned or considered; (5) Maternal diagnosis of placenta 
previa, accreta, or abruption; (6) Maternal diagnosis of pre-eclampsia requiring 
Magnesium sulfate therapy at time of delivery (7) OB or Neonatal provider concerns 
for the clinical care of the mother or infant or study team not available. 
Study Interventions and Measures:  
 DING Intervention: Immediately after birth, the infant will be placed on a Lifestart 
trolley with an intact umbilical cord, intubated, and ventilated with the CHOP 
“gentle ventilation” protocol.  UCC will occur after (1) colorimetric end-tidal CO2 
detection or (2) 3 minutes after delivery, whichever occurs first. 
 Primary Outcome: Successful protocol completion (defined as infant 
successfully intubated prior to UCC).  
 Secondary outcomes: Arterial pH and PaO2 on first blood gas, Oxygenation 
index [OI] throughout first 24 hours of life [HOL], need for vasopressors (first 24 

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HOL), presence of severe pulmonary hypertension on first echocardiogram, 
need for ECMO and mortality during hospital discharge. 
 Tertiary outcomes: Identification of salient themes in parent experiences of the 
DING intervention, Identification of factors during the intervention that mothers 
identify as stress inducing or alleviating.

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PROTOCOL SYNOPSIS 
Study Title 
Delayed Cord Clamping for Intubation and Gentle Ventilation 
in Infants with Congenital Diaphragmatic Hernia: A Pilot 
Feasibility Trial 
Funder 
Departmental funds 
Study Rationale 
Infants with CDH are at risk for pulmonary hypoplasia and 
pulmonary hypertension and often experience hypoxemia and 
acidosis during neonatal transition.  The standard approach to 
DR resuscitation is immediate UCC followed by intubation 
and mechanical ventilation.  Animal models suggest that 
achieving lung aeration prior to UCC results in improved 
pulmonary blood flow and cardiac function compared with 
immediate UCC before lung aeration is established. Trials of 
preterm infants demonstrated that initiating respiratory 
support prior to UCC is safe and feasible.  Because infants 
with CDH are at high risk for pulmonary hypertension and 
systemic hypotension, they may benefit from the 
hemodynamic effects of lung aeration before UCC, namely 
increased pulmonary blood flow, decreased pulmonary 
vascular resistance, and improved cardiac output.  To date, 
this approach has not been studied in infants with CDH.   
Study Aims 
Primary  
To determine the safety and feasibility of performing delayed 
cord clamping for intubation and initiation of ventilation in 
infants with congenital diaphragmatic hernia. 
 
Secondary 
To characterize short-term hemodynamic and respiratory 
outcomes among infants with CDH who are treated with 
intubation and ventilation prior to UCC and to compare these 
outcomes with historical control infants with CDH who were 
treated with immediate UCC prior to intubation. The historical 
controls will be identified from IRB #3799. 
 
Tertiary 
To characterize maternal experiences and perspectives of 
delayed cord clamping until after intubation and lung aeration 
are established in the infant 
Test Article(s) 
The study intervention is the DING procedure: Immediately 
after birth, the infant will be placed on a Lifestart trolley with 
an intact umbilical cord, intubated, and ventilated with the 
CHOP “gentle ventilation” protocol.  UCC will occur after (1) 
colorimetric end-tidal CO2 detection or (2) 3 minutes after 
delivery, whichever occurs first. 

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Study Design 
This is a single site single-arm open-label interventional trial. 
Subject Population 
 
The inclusion and exclusion criteria are identical for the DCC 
arm and the historical controls 
Inclusion Criteria-  
1. Antenatal diagnosis of CDH, with care in the Center for 
Fetal Treatment  
2. Gestational age ≥ 36 weeks at birth 
Exclusion Criteria 
1. Multiple gestation 
2. Major anomalies or aneuploidy 
3. Enrolled in FETO trial (fetal endoluminal tracheal 
occlusion) 
4. Palliative care planned or considered 
5. Maternal diagnosis placenta previa, accreta, or 
abruption 
6. Maternal diagnosis of pre-eclampsia requiring 
Magnesium sulfate therapy at time of delivery 
7. OB or Neonatal provider concerns for the clinical care 
of the mother or infant, or study team not available. 
Number Of Subjects 
We will allocate 20 infant-mother dyads in this pilot feasibility 
trial and 20 infant-mother dyads for the historical controls. 
Study Duration 
Each subject’s participation will last from birth until hospital 
discharge 
Study Phases 
  
This is an open-label single-arm interventional trial 
 Screening Phase will take place on an antenatal basis, 
during prenatal visits to the CHOP Center for Fetal 
Diagnosis and treatment or upon admission to the SDU.  
Mothers of potentially eligible infants will provide informed 
consent during the screening phase. 
 Study Treatment Phase: Prior to and during delivery, 
eligibility criteria will be reviewed.  Eligible infants will 
receive the study intervention during the first 3 minutes of 
life. 
 Follow up Phase: Follow up will continue until hospital 
discharge. 
Efficacy Evaluations 
The primary endpoint will be successful completion of the 
DING intervention.  Infants who are intubated and have 
ventilation initiated prior to UCC and prior to 3 minutes of life 
will be considered to have successfully completed the 
protocol.  

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Secondary endpoints: Arterial pH and PaO2 on first blood gas, 
Oxygenation index [OI] throughout first 24 hours of life [HOL], 
need for vasopressors (first 24 HOL), presence of severe 
pulmonary hypertension on first echocardiogram.  Need for 
ECMO during hospitalization, mortality prior to discharge. 
Tertiary endpoints: Identification of salient themes in parent 
experiences of the DING intervention, Identification of factors 
during the intervention that mothers identify as stress inducing 
or alleviating. 
Safety Evaluations 
Safety evaluations will include:  
Neonatal evaluations: cord avulsion, need for chest 
compressions during resuscitation, hypothermia on first 
temperature in the SDU  
Maternal evaluations: post-partum hemorrhage, need for 
therapeutic uterotonics, estimated blood loss, contamination 
of sterile obstetrical field, wound infection 
Statistical And 
Analytic Plan 
Baseline characteristics, the primary, secondary, and tertiary 
endpoints, and safety evaluations will be summarized by 
standard descriptive summaries. 
Secondary outcomes will be compared with historical controls 
using bivariable analyses 
Data and Safety 
Monitoring Plan 
An independent data and safety monitoring board will review 
outcomes incrementally after allocation of every 5 subjects to 
ensure the study does not impose undue extra risk to treated 
subjects. 

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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Congenital diaphragmatic hernia (CDH) is a congenital anomaly associated with a 
high risk of mortality (29%) and need for life-saving interventions such as ECMO 
(33%), nitric oxide (62%), and vasopressor support (73%).1   Although infants with 
CDH experience significant morbidity and mortality starting immediately after birth, 
high quality evidence informing delivery room resuscitation in this population is 
lacking. 
Infants with CDH are at risk for pulmonary hypoplasia and pulmonary hypertension 
and often experience hypoxemia and acidosis during neonatal transition.  The 
standard approach to DR resuscitation is immediate UCC followed by intubation 
and mechanical ventilation.  The goals of this strategy are to immediately recruit 
and aerate the lung for gas exchange and oxygenation, while simultaneously 
avoiding gaseous distention of the thoracic gastrointestinal contents. 
Animal models suggest that achieving lung aeration prior to UCC results in 
improved pulmonary blood flow and cardiac function compared with immediate UCC 
before lung aeration is established. Trials of preterm infants demonstrated that 
initiating respiratory support prior to UCC is safe and feasible.  Because infants with 
CDH are at high risk for pulmonary hypertension and systemic hypotension, they 
may benefit from the hemodynamic effects of lung aeration before UCC, namely 
increased pulmonary blood flow, decreased pulmonary vascular resistance, and 
improved cardiac output.   
We hypothesize that a sequence of intubation, gentle ventilation, and then umbilical 
cord clamping will result in improved cardiovascular transition after birth in infants 
with CDH.  To date, this approach has not been studied in infants with CDH.   
 
The DING trial will assess the feasibility and safety of this intervention in infants with 
CDH. The DING trial will also characterize short-term hemodynamic and respiratory 
outcomes among infants with CDH who are treated with intubation and ventilation 
prior to UCC and to compare these outcomes with historical control infants with 
CDH who were treated with immediate UCC prior to intubation 
 
1.2 Name and Description of Investigational Intervention: 
We will study the “DING” intervention: Delayed cord clamping for INtubation and 
Gentle ventilation.   
In this intervention, the infant will undergo intubation and initial ventilation with an 
intact umbilical cord.  Once lung aeration is established (as indicated by colorimetric 
CO2 detection), the umbilical cord will be clamped, and the infant will be moved to 
the resuscitation suite for ongoing stabilization. 

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1.3 Relevant Literature and Data 
1.3.1 Delayed Cord Clamping 
1.3.1.1 Recommendations for Delayed Cord Clamping  
Delayed cord clamping after birth is now recommended for infants who do not 
require resuscitation by multiple professional organizations (Table 1).  Because the 
standard practice for infants with CDH is immediate intubation and ventilation, DCC 
is not performed in these infants, and the effects of DCC in this population remain 
unstudied. 
Organization 
Year 
Recommendations 
World Health Organization (WHO) 2  
2012 
In term or preterm babies who do not require 
positive-pressure ventilation, the cord should not be 
clamped earlier than 1 minute after birth 
Neonatal Resuscitation Program (NRP) 3 
2015 
DCC (>30 seconds) for preterm and term infants who 
do not require resuscitation 
American College Obstetrics and 
Gynecology (ACOG), endorsed by 
American Academy of Pediatrics (AAP) 4 
2017 
Evidence supports DCC in vigorous term and 
preterm infants for at least 30-60 seconds after birth 
Table 1: Professional Organizations: Recommendations for Delayed Cord Clamping  
1.3.1.2 Physiologic Effects of Delayed Cord Clamping 
Potential physiologic benefits from DCC result from both placental transfusion and 
improved cardiovascular transition at birth. 
Placental Transfusion: DCC allows for ongoing redistribution of blood from the 
placenta to the fetus after birth, resulting in higher hemoglobin levels immediately 
after birth and improved iron stores throughout infancy.5 
Cardiovascular Transition: There are potential hemodynamic benefits associated 
with DCC.  Immediately after birth, lung aeration triggers a reduction in pulmonary 
vascular resistance and increase in pulmonary blood flow.6,7  At the same time, 
clamping the umbilical cord and removing the low-resistance placental circuit results 
in increased systemic vascular resistance.  These changes trigger the transition 
from the fetal to post-natal circulation. 
However, clamping the umbilical cord prior to lung aeration may impair cardiac 
output due to a combination of decreased preload and increased afterload:8 
 Decreased preload: In utero, umbilical venous blood is the major contributor to 
left ventricular preload.  Once lung aeration occurs, the increased pulmonary 
blood flow results in adequate venous return to the left heart.  However, if UCC 
occurs prior to lung aeration, umbilical venous blood flow is removed prior to the 
requisite increase in pulmonary blood flow, resulting in impaired preload. 
 Increased afterload:  UCC causes an increase in systemic peripheral resistance, 
which results in increased afterload. 
Combined, these processes can result in up to 50% decrease in cardiac output.9   

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Most infants breathe independently after birth and do not require resuscitation. For 
these infants, DCC allows for lung aeration (from spontaneous respirations) to be 
established prior to UCC.  Current recommendations for non-vigorous infants call 
for immediate UCC to facilitate initiation of resuscitation and positive pressure 
ventilation (Table 1).  However, infants who do not independently aerate their lungs 
may benefit from initiating resuscitation to establish lung aeration prior to umbilical 
cord clamping.  Thus, there is an active line of investigation to determine the impact 
of aerating the newborn lung prior to UCC among infants who require respiratory 
support for neonatal resuscitation.   
1.3.2 Animal models 
Bhatt et al studied the impact of establishing ventilation before umbilical cord 
clamping in preterm lambs.10  Compared with UCC followed by ventilation, 
establishing ventilation prior to UCC resulted in fewer fluctuations in carotid arterial 
pressure, less bradycardia and improved pulmonary blood flow in the first minutes 
after cord clamping (Figure 1).  
  
Figure 1: Pulmonary blood flow in first 2 minutes after cord clamping in preterm lambs. 
10   
In addition, Polglase et al. studied the impact of ventilation prior to cord clamping on 
oxygenation and hemodynamics in preterm lambs.11  Compared with lambs who 
were ventilated after UCC, lambs who were ventilated prior to UCC required 
significantly lower concentrations of inspired oxygen to maintain similar tissue 
oxygenation saturations after cord clamping. 
  
1.3.3 Clinical trials in preterm infants 
The available clinical evidence for of initiation of respiratory support during DCC 
comes from trials of preterm infants (Table 2).  These trials vary in design but share 
the basic principle of initiating non-invasive respiratory support for preterm infants 
with an intact umbilical cord.  
Trial 
Design 
Population 
Intervention 
   Ventilated prior to cord clamping 
 
 Not ventilated prior to cord clamping 
 

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Katheria, 2016 12 
Single site 
RCT 
N=150 infants  
GA: 23 0/7 – 31 6/7 weeks  
125 C-Section, 25 vaginal 
60s DCC + respiratory support as 
needed 
vs.  
60 s DCC +/- stimulation  
Winter, 2016 13 
Single site 
feasibility 
trial 
N=29 infants  
GA: 24-32 6/7 weeks  
21 C-Section, 8 vaginal 
Single Arm:  
90s DCC plus respiratory support 
(CPAP or PPV) 
Kattwinkel 
(ongoing)14 
Multi-site 
RCT 
 
Target n=940 infants 
GA: 23-286/7 weeks 
120s DCC + CPAP or PPV  
vs.  
30-60s DCC +/-stimulation  
Pushpa-Raja 
(ongoing)15 
Multi-site 
RCT 
Target n=100 
infant/mother pairs 
GA <32 weeks 
120s DCC, with ‘initial care’ provided 
during DCC 
vs.  
UCC after 20s 
Table 2: Trials of preterm infants undergoing resuscitation with an intact umbilical cord 
Abbreviations: CPAP: continuous positive airway pressure; DCC: delayed cord clamping; GA: 
gestational age; PPV: positive pressure ventilation; RCT: randomized controlled trial 
 
Of the combined 179 infants enrolled in the Katheria and Winter trials, 171 (96%) 
infants completed the assigned study protocol. Importantly, neither trial reported 
adverse events or safety concerns among infants who treated with respiratory 
support prior to UCC.  Among the 8 infants who did not complete the full protocol in 
Katheria’s trial, the umbilical cord was clamped early due to the obstetrical 
assessment that the infant was too unstable.   
These preliminary data demonstrate that providing respiratory support with an intact 
umbilical cord is feasible and safe in preterm infants.  However, a key difference in 
the current DING trial is that infants in the preterm trials were not intubated for 
resuscitation prior to UCC.  A major logistical challenge to intubating infants with an 
intact cord relates to whether the umbilical cord is long enough to allow for 
appropriate positioning for intubation.  Other authors have reported successful 
intubation prior to UCC in a limited number of preterm infants 16.  In addition, the full 
term umbilical cord is longer than the preterm umbilical cord (Table 3), which would 
allow more room to maneuver and position a full term infant for intubation.   
In summary, pre-clinical evidence suggests that establishing lung aeration prior to 
UCC results in improved cardiovascular transition after birth.  Further, performing 
resuscitation via non-invasive facemask with an intact umbilical cord is safe and 
feasible in preterm infants.  A strategy of intubation and ventilation prior to UCC in 
infants with CDH has not been studied.  This trial will determine the safety and 
feasibility of delayed cord clamping for intubation and gentle ventilation for full term 
infants with CDH. 

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1.4 Compliance Statement 
This study will be conducted in full 
accordance all applicable Children’s 
Hospital of Philadelphia Research Policies 
and Procedures and all applicable Federal and state laws and regulations including 
45 CFR 46.  All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
parental consent (unless a 'waiver of consent is granted) and will report 
unanticipated problems involving risks to subjects or others in accordance with The 
Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal 
requirements. A waiver of assent will be obtained since subjects are infants. 
Collection, recording, and reporting of data will be accurate and will ensure the 
privacy, health, and welfare of research subjects during and after the study.  
2 
STUDY OBJECTIVES 
2.1 Primary Aim  
The primary objective of this study is to determine the safety and feasibility of the 
DING intervention (Delayed cord clamping for INtubation and Gentle ventilation) for 
full term infants with CDH.  
2.2 Secondary Aim 
The secondary objective is to characterize short-term hemodynamic and respiratory 
outcomes among full term infants with CDH who are treated with intubation and 
ventilation prior to UCC and to compare these outcomes with historical control 
infants with CDH who were treated with immediate UCC prior to intubation. 
 
2.3 Tertiary Aim 
To ascertain the mother’s experience and perspectives of delayed cord clamping 
until after intubation and lung aeration are established in the infant. 
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This is an open-label single-site single-arm interventional trial at the Children’s 
Hospital of Philadelphia.  
3.1.1 Screening Phase 
Potential subjects will be screened on an antenatal basis in the CHOP Center for 
Fetal Diagnosis and Treatment (CFDT) and the SDU.  We will identify and screen 
all women carrying a fetus at least 32 weeks gestation with a prenatal diagnosis of 
Gestational Age 
N 
Umbilical cord length, 
cm mean (SD) 
24-25 weeks 
38 
40.1 (10.1) 
26-27 weeks 
59 
42.5 (11.3) 
28-29 weeks 
80 
45.0 (9.7) 
30-31 weeks 
113 
47.6 (11.3) 
32-33 weeks 
337 
50.2 (12.1) 
34-35 weeks 
857 
52.5 (11.2) 
36-37 weeks 
3,153 
55.6 (12.6) 
38-39 weeks 
10,083 
57.4 (12.6) 
40-41 weeks 
13,841 
59.6 (12.6) 
Table 3: Mean umbilical cord length (cm), according to 
gestational age, from Naeye et al.17  

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CDH who plan to deliver in the CHP SDU. We will approach the parents during a 
prenatal visit at the CFDT or on an antenatal inpatient basis in the SDU to offer 
study participation and obtain informed consent.  Given that the subjects are 
neonates, we will not obtain assent.     
For fetuses with parental consent, we will then review the eligibility criteria again 
prior to and during delivery.  Subjects with signed antenatal informed consent who 
meet all eligibility criteria will be allocated to the trial intervention at the time of birth. 
3.1.2 Study Treatment Phase (start of the study intervention) 
At the time of delivery, if the infant meets all eligibility criteria, the infant will be 
allocated to receive the DING intervention.  The study treatment phase will last up 
to 3 minutes, after which point the infant will be moved to the SDU infant 
resuscitation suite and for ongoing standard-of-care clinical resuscitation. 
3.1.3 Follow-up Phase 
The follow-up phase will continue until hospital discharge.  In this phase we will 
assess the infant’s physiologic outcomes and the mother’s perspectives of the 
DING intervention.  Questionnaires will be administered to mothers who consent to 
participation in the DING trial from day 1 to 1 month post-partum.  A study team 
member will also approach within 1 month of the infant’s birth for an approximately 
30 minute open-ended in-person interview. 
    
3.2 Allocation to Treatment Groups and Blinding 
This is an open-label single-arm interventional trial.  All enrolled and eligible infants 
will be allocated to the DING study intervention. 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
Screening and informed consent will take place up to 8 weeks prior to birth.   
Once subjects are considered eligible, the intervention will take no more than 3 
minutes. The follow up phase will last until hospital discharge. For allocated infants, 
the duration of study participation is therefore from birth until discharge. 
 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at the Children’s Hospital of Philadelphia.  Recruitment 
will stop when 20 infant-mother dyads are allocated to receive the study 
intervention.The total number of subjects is 40 infant-mother dyads, which includes 
the 20 historical controls. 
3.4 Study Population 
3.4.1 Inclusion Criteria 
1. Antenatal diagnosis of CDH, with care in the Center for Fetal Treatment  
2. Gestational age ≥ 36 weeks at birth 

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3.4.2 Exclusion Criteria 
1. Multiple gestation 
2. Major anomalies or aneuploidy 
3. Enrolled in FETO (fetal endoluminal tracheal occlusion) trial 
4. Palliative care planned or considered 
5. Maternal diagnosis placenta previa, accreta, or abruption 
6. Maternal diagnosis pre-eclampsia requiring Magnesium sulfate therapy at 
time of delivery 
7. OB or Neonatal provider concerns for the clinical care of the mother or infant, 
or study team not available. 
 
The inclusion and exclusion criteria are the same for the interventional arm and the 
historical controls. Subjects that do not meet all of the enrollment criteria may not be 
enrolled. Any violations of these criteria must be reported in accordance with IRB 
Policies and Procedures.  
4 
STUDY PROCEDURES 
4.1 Screening Visit 
o We will screen for potential subjects during antenatal visits in the 
CFDT and on an antenatal basis for women admitted to the SDU.  The 
screening visit includes: 
o Medical Record Review 
o Informed Consent 
o The historical controls will be identified from IRB # 3799 and will be 
selected as the most recent historical control, matched for gestational 
age and CDH severity markers to allocated subjects in the 
interventional arm. 
4.2 Study Treatment Phase 
4.2.1 Visit 1: Delivery visit 
The delivery visit occurs when mothers of fetuses with informed consent present for 
delivery.  The delivery visit includes:   
o Medical Record Review 
o Study intervention 
o Video Recording of Resuscitation 
 
4.2.2 Matched Historical Controls 
Medical record review will include the specified secondary clinical outcomes 
for control infants. 
 

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4.3 Follow-up Phase  
The follow up phase will occur for until hospital discharge and includes  
 Medical Record Review 
In the follow up phase, we will also ascertain the maternal experience and 
perspectives of participating in the DING intervention through:  
 Maternal questionnaire administration 
 Semi-structured maternal interview  
Maternal perspectives will be ascertained through a questionnaire administered to 
the mother within the first month post-partum.   The DING questionnaire will be 
provided to mothers while they are visiting their infants in the NICU.  At that point, 
mothers can opt in to participate in a semi-structured interview to further explore 
their experience and views in a qualitative fashion.  The interview will take place 
within the first month of delivery. 
 
4.4 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care. 
The Investigator may also withdraw subjects to protect the subject for reasons of 
safety or for administrative reasons.   
It will be documented whether or not each subject completes the clinical study.  
If the Investigator becomes aware of any serious, related adverse events after the 
subject completes or withdraws from the study, they will be recorded in the source 
documents and on the CRF. 
 
4.4.1 Early Termination Study Visit 
All study procedures will occur during the birth hospitalization, on an inpatient basis. 
There is no specific early termination study visit for subjects who withdraw from the 
study.   
 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Identification of eligible subjects 
A study team member will search for patients meeting inclusion and exclusion 
criteria by reviewing, but not obtaining or recording, data from the Epic 
electronic health record to determine if patients are potentially eligible. Patients who 
are preliminarily identified as possibly eligible will be placed on a screening log that 
is locked in a file cabinet in a locked research office. The historical controls will 
come from IRB # 3799. 
 

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5.2 Screening and Monitoring Evaluations  
5.2.1 Medical Record Review – for both interventional arm and historical 
controls 
We will abstract the following variables from the maternal and infant chart: 
 Baseline characteristics 
o Prenatal ultrasound findings 
o Gestational age at prenatal diagnosis 
o Date of birth 
o Time of birth 
o Mode of delivery 
o Gestational age 
o Birth weight 
o Sex 
o Race 
o Ethnicity 
 Type and timing of resuscitation interventions in the delivery suite and SDU:  
o Intubation 
 Number of attempts 
 Time of successful intubation 
 Tracheal intubated adverse events, using NEAR4Neos 
operational definitions 
o Interval between birth and UCC (for interventional arm only) 
o Chest compressions performed 
o Medications and fluids administered  
o Supplemental FiO2 
o Ventilator settings 
o Vital signs during resuscitation (temperature, heart rate, respiratory 
rate, blood pressure, pulse oximetry) 
 Cardiorespiratory Interventions and diagnostic tests in first 7 days of life 
o Vital signs (heart rate, pulse oximetry, blood pressure) 
o Supplemental FiO2 
o Ventilator settings 
o Vasopressors (type and dose) 
o Laboratory tests (blood gasses, complete blood count, bilirubin level) 
o Echocardiogram findings 
 Clinical outcomes during hospitalization 
o ECMO cannulation (occurrence and day of life) 
o Mortality (occurrence, day of life, and cause) 
 Maternal chart review (outcomes will be ascertained in first 7 days after 
delivery, or until discharge- whichever period is shorter – for interventional 
arm only)  
o Estimated blood loss at delivery (all deliveries) 
o Need for therapeutic uterotonics (all deliveries) 
o First post-partum hemoglobin (all deliveries) 

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o OR time (for Cesarean deliveries) 
o Contamination of sterile field (for Cesarean deliveries) 
o Surgical wound infection (for Cesarean deliveries) 
5.2.2 Video Recording 
Video recording is clinical standard of care for post-delivery resuscitation in the 
SDU.  These clinically obtained videos will be reviewed as additional source 
documentation to confirm the sequence and timing of resuscitative interventions 
performed after the DING intervention.  
In addition, we will mount a CHOP-owned portable video camera to the LifeStart 
trolley to record the DING intervention as it is performed. 
5.2.3 Laboratory Evaluations 
No specific laboratory evaluations will be obtained specifically for this study.  We will 
abstract data from the following laboratory tests, which are obtained as part of 
standard clinical care: 
 Arterial blood gasses obtained in SDU and in the first 24 hours of life 
 Hemoglobin from admission CBC 
 Peak bilirubin level in first week of life 
5.3 Efficacy Evaluations 
The primary outcome is successful completion of the DING intervention.  After each 
infant is allocated to the intervention, the study team will review the resuscitation 
video and the medical record and will discuss the intervention with the resuscitation 
team.  The manual of operations will be iteratively refined based on these findings.  
The following measures related to protocol feasibility will be documented: 
 Infant successfully positioned on the table 
 Successful intubation prior to cord clamping 
o If not: why not 
 Number of intubation attempts 
 Duration of time between birth and cord clamping 
5.4 Safety Evaluation 
Subject safety will be monitored through medical record review and debriefing the 
clinical staff.  We will monitor for the following; 
 Neonatal outcomes: 
o Cord avulsion 
o Need for chest compressions during resuscitation 
o Hypothermia (first documented temperature in the SDU <36.0) 
 Maternal outcomes: 
o Any potential contamination of sterile obstetrical field 
o Surgical wound infection 
o Post-partum hemorrhage 
o Estimated blood loss 

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o Need for therapeutic uterotonics 
 Any additional concerns from Obstetrical or Neonatal staff 
5.5 Evaluation of Maternal Perspectives: 
All interviews will be audio-recorded. 
Questionnaires will include questions pertaining to the following topics: 
 
How well-prepared for the intervention mothers felt 
 
Whether they felt staff gave good explanations during the intervention 
 
Whether they understood the interventions taking place 
 
Whether they felt the intervention was traumatic or stressful, increased worry, 
provided reassurance 
 
Whether they would want to be in close proximity again should they be 
presented with a similar situation 
Interview questions will address the following topics: 
 
How the experience in the delivery room could have been improved 
 
If there are things that could have been explained ahead of time that would 
have resulted in an improved experience 
 
How parents felt while their babies were being intubated 
 
The impact of having additional providers in the delivery room 
 
STATISTICAL CONSIDERATIONS 
5.6 Primary Endpoint 
The primary endpoint will be successful completion of the DING intervention for 
those subjects allocated to the interventional arm of the study.  Infants who are 
intubated and have ventilation initiated prior to UCC and prior to 3 minutes of life will 
be considered to have successfully completed the protocol 
. 
5.7 Secondary Endpoints 
Secondary endpoints include arterial pH and PaO2 on first blood gas, oxygenation 
index [OI] throughout first 24 hours of life [HOL], need for vasopressors (first 24 
HOL), presence of severe pulmonary hypertension on first echocardiogram, need 
for ECMO and mortality during hospitalization for both the subject allocated to the 
interventional arm and the historical controls.  
 
5.8 Tertiary Endpoints:  
Identification of salient themes in parent experiences of the DING intervention, 
Identification of factors during the intervention that mothers identify as stress 
inducing or alleviating. 
 

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5.9 Statistical Methods 
5.9.1 Baseline Data  
Baseline characteristics, the primary, secondary, and tertiary endpoints, and safety 
evaluations will be summarized by standard descriptive summaries.   
 
5.9.2 Primary Analysis 
The primary analysis will be based on an intention to treat approach.  All infants 
who meet all eligibility criteria at the time of birth and are allocated to the 
intervention are considered evaluable.  The proportion of evaluable infants who 
successfully complete the DING intervention will be reported as the primary 
outcome.   
 
5.9.3 Secondary Outcomes 
We will compare secondary clinical outcomes between evaluable DING participants 
and evaluable historical controls who are enrolled in the Pulmonary Hypoplasia 
Program (PHP) registry (IRB#06-003779).   
Controls will be identified from the CHOP Pulmonary Hypoplasia Program registry, 
which contains detailed information about infants with CDH treated at CHOP. For 
each DING participant, we will select the most recent historical control, matched for 
gestational age and CDH severity markers. Matched historical controls will be 
considered evaluable if they meet all inclusion and exclusion criteria and their 
medical record is complete for comparison. 
We will ascertain the specified secondary clinical outcomes for control infants.  The 
data for the controls will come from the PHP registry (IRB # 3799). 
 
We will compare the short-term outcomes between groups, using Student’s t test or 
Wilcoxon rank sum test for continuous variables and chi square or Fisher’s exact 
test for dichotomous variables.   
  
5.9.4 Safety Analysis 
All subjects who have been allocated to the DING intervention will be included in the 
safety analysis. The frequencies of AEs will be summarized. SAEs (if any) will be 
described in detail. 
 
5.9.5 Qualitative Analysis of Maternal Perspectives 
We will use qualitative methods to identify thematic maternal responses to the DING 
intervention. Summary statistics will be used to describe parental responses to the 
questionnaire items.  In an exploratory analysis, we will also compare responses 
between mothers who choose to have a screen in place during the DING 
intervention and those who do not if there are sufficient respondents in each group 
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that we will be able to draw firm conclusions from such comparisons but we may be 
able to identify trends.  Recordings of the interviews will be sent to the ADA 
transcription services for transcription. Transcripts will be coded and analyzed by 
CHOP study team members. These codes will be defined and entered into the 
project data dictionary and will ultimately applied to all transcripts.  We will then 
explore for thematic responses in the open ended interviews.  We will investigate for 
common themes related to parent descriptions of modifiable factors that mothers 
identify as impacting their experiences, again working to identify, describe, and 
analyze key themes. 
 
5.10 Sample Size and Power 
We will enroll 25 mother-infant dyads in this pilot feasibility trial in order to obtain 20 
evaluable subjects.  The DING intervention has not been previously studied in 
infants with CDH, so the objective of this trial is to determine the feasibility of this 
intervention.  A sample size of 20, consistent with other delivery room feasibility 
trials,13,18 was selected to permit adequate assessment of feasibility.  In addition, 
review and comparison of secondary outcomes will inform power analyses for a 
subsequent RCT of clinical outcomes.  Since this is a pilot study, we do not 
anticipate finding statistically significant differences, though clinically significant 
differences may be observed.  Instead, the analytic aims are to obtain estimates 
needed for designing future randomized trials of the DING intervention. 
 
Approximately 40-50 infants with CDH are born in the SDU per year, ensuring the 
recruitment goal is feasible. 
5.11 Interim Analysis 
An independent data and safety monitoring board (DSMB), comprising a clinical 
epidemiologist and two clinical content experts, will review specified safety events 
incrementally after allocation of every 5 subjects to ensure the study does not 
impose undue extra risk on infants with CDH.  
As this is a single-arm trial, there are no early 
stopping rules for efficacy. 
 
6 
STUDY INTERVENTION 
6.1 Description 
All eligible infants will be allocated to receive the 
DING intervention.  Immediately after birth, the infant 
will be placed on a LifeStart trolley with an intact 
umbilical cord, intubated, and ventilated according to 
the CHOP clinical “Gentle ventilation” protocol.  UCC 
will occur after (1) colorimetric end-tidal CO2 
Figure 2: Team simulation of DING 
intervention during vaginal delivery, using 
Lifestart Trolley 

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detection or (2) 3 minutes after delivery, whichever occurs first. 
DCC has been variably defined in studies, using a time-based approach (ranging 
from 1-5 minutes) or physiologic approach (ie: cessation of cord pulsation, or 
placental descent). 5  An upper limit of 3-minutes prior to UCC was selected through 
discussion with the clinical team, as this interval would to allow sufficient time for the 
neonatal team to establish lung aeration prior to placental separation, while also 
avoiding a delay in transferring the infant to the infant stabilization suite. A 
retrospective review of intubations performed at CHOP demonstrated a 62% first-
attempt success rate for attending neonatologists, and over 85% of attending 
neonatologists were successful within the first 2 intubation attempts.19 Thus, we 
anticipate that 3 minutes is a sufficient time period for most DING trial participants to 
be successfully intubated prior to UCC. 
The Lifestart trolley is a small resuscitation trolley specifically designed to facilitate 
neonatal resuscitation with an intact umbilical cord.  The trolley includes a warmer 
mattress and has FDA 510K clearance (See attachment). The CHOP Medical 
Device Committee approved the Lifestart trolley for use in this DING trial.  The 
trolley will be positioned next to the mother covered in a sterile drape prior to the 
delivery.  The senior neonatal clinician (who will perform the intubation and is a 
member of the study team), the neonatal nurse, and the neonatal respiratory 
therapist will all attend the infant during the DING intervention.   
Immediate cord clamping will be performed for any of the following: 
 Inadequate umbilical cord length or inability to adequately position infant on the 
trolley for intubation  
 If the neonatologist or obstetrician has any concerns about the infant or mother’s 
safety or the team’s ability to perform clinical interventions 
Team coordination: 
The DING intervention requires complex coordination of providers across many 
disciplines.  We have performed multidisciplinary simulations (including 
neonatology, obstetrics, nursing, respiratory therapy) to determine the optimal 
placement of providers and equipment to perform the DING intervention while 
ensuring mother and infant safety. Study team neonatologists will perform DING 
study procedures. (Figure 2). 
 
7 
SAFETY MANAGEMENT 
7.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  Given the 
short duration of the study intervention, we will monitor adverse events that occur in 
the SDU setting and in the ensuing 24 hours (the Follow Up phase).   
Because of the disease severity and protocol-driven clinical interventions for the 
study population, we will not classify the following events (which are typical and 
expected in the CDH population in the first 24 hours of life) as SAEs: mechanical 
ventilation, inotropic medications, or iNO. 

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7.2 Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others 
that occur during the course of this study (including SAEs) will be reported to the 
IRB in accordance with CHOP IRB SOP 408: Unanticipated Problems Involving 
Risks to Subjects. AEs that are not serious but that are notable and could involve 
risks to subjects will be summarized in narrative or other format and submitted to 
the IRB at the time of continuing review.   
7.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has 
received an intervention (drug, biologic, or other intervention).  The occurrence does 
not necessarily have to have a causal relationship with the treatment.  An AE can 
therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case 
report form with a full description including the nature, date and time of onset, 
determination of non-serious versus serious, intensity (mild, moderate, severe), 
duration, causality, and outcome of the event. 
7.4 Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse experience that results in any of the following outcomes:  
 death, 
 a life-threatening event (at risk of death at the time of the event),  
 requires inpatient hospitalization or prolongation of existing hospitalization, 
 a persistent or significant disability/incapacity, or 
 a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a 
major event of its type.  A severe AE does not necessarily need to be considered 
serious.  For example, nausea which persists for several hours may be considered 
severe nausea, but would not be an SAE.  On the other hand, a stroke that results 
in only a limited degree of disability may be considered a mild stroke, but would be 
an SAE.  
7.4.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention should be characterized 
using one of the following terms in accordance with CHOP IRB Guidelines: 
definitely, probably, possibly, unlikely or unrelated.  

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7.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious 
Adverse Events that are related to the research activity. Other unanticipated 
problems related to the research involving risk to subjects or others will also be 
reported promptly. Written reports will be filed using the eIRB system and in 
accordance with the timeline below.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, 
Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life 
Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
7.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information 
arises that changes the investigator’s assessment of the event, a follow-up report 
including all relevant new or reassessed information (e.g., concomitant medication, 
medical history) should be submitted to the IRB. The investigator is responsible for 
ensuring that all SAE are followed until either resolved or stable.  
 
8 
STUDY ADMINISTRATION 
8.1 Treatment Assignment Methods 
8.1.1 Randomization 
This is a non-randomized trial.   
8.1.2 Blinding 
This is an unblinded trial.  
8.2 Data Collection and Management 
All data management will be consistent with CHOP Policy A-3-6: Acceptable Use of 
Technology Resources: 
1. Confidentiality.  Coded data will be collected on data collection forms. A master 
list containing any identifying PHI and subject ID number will be kept separate 
from the data forms. Subjects will be identified in the study database by study ID 
only.  The master list will be kept in in a locked office.  

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2. Security.  A copy of the password protected master code will be kept in a 
password-protected file on the PI’s office computer, which is kept in a locked 
office.  Coded data collected on the data forms will be entered as a limited 
dataset into the Redcap database, a password protected secure internet-based 
database.  User’s rights to the dataset will be limited to the study PI and study 
coordinator.  The hard copy of the data collection forms will be kept in a locked 
file cabinet, separate from the master file. 
3. Anonymization, de-identification or destruction. The master file linking subjects’ 
PHI to subject ID numbers will be destroyed according to CHOP’s A-3-9 policy 
for Human Subjects Research which states 10 years earlier from age 18 or 
death; or longer period required by sponsor.  
4. Video recordings: Recordings will be maintained in a password-protected file on 
the study PI’s password-protected office computer, which is kept in a locked 
office or CHOP secure server.  Video recordings will be destroyed as soon as 
data analysis is complete.  
5. Audio files: Audio recordings will be kept in a locked cabinet in a locked office.  
Interviews will be recorded with a hand held recorder and audio files will be 
uploaded to the secure ADA transcription website, and/or the ADA call-in service 
will be used for direct recording and transcription. Audio recordings will be stored 
on a password protected computer prior to being transferred via the secure 
website.  To the best of our ability, names, titles, conditions, and any possible 
identifying information of participants will not be recorded.  In order to minimize 
recording of identifiable information, the participant will be told to refrain from 
using names or any other identifiable information before the recorded interview 
takes place.  ADA maintains strict confidentiality when working with research 
studies and their participants and will remove any identifiable information, should 
participants reference anything identifiable, from the transcript. Transcripts will 
be reviewed after received from ADA and scrubbed for any possible remaining 
identifying information before they are uploaded to qualitative software for 
analysis. There will be no linkage of participants to their quotes in the final 
manuscript, thus obscuring the identity of individuals.  All interview-related 
materials, including audio, transcripts, study information, documentation, and 
any other materials received by or created for the interview portion of the project, 
are safely sand securely kept and maintained while under the possession of the 
study team and ADA Transcription. ADA transcription guarantees that all audio 
files and transcripts for this study will be completely deleted two weeks after 
payment for transcripts are received. All study-related information and 
documentation held by ADA is then deleted within three weeks of payment. This 
includes hard drives, backup drives, and any all device copies that may exist.  
The study team will maintain a copy of the de-identified interviews in accordance 
with CHOP policy. 
8.3 Confidentiality 
All data and records generated during this study will be kept confidential in 
accordance with Institutional policies and HIPAA on subject privacy and that the 

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Investigator and other site personnel will not use such data and records for any 
purpose other than conducting the study.  
No identifiable data will be used for future study without first obtaining IRB approval. 
The investigator will obtain a data use agreement between the provider (the PI) of 
the data and any recipient researchers (including others at CHOP) before sharing a 
limited dataset.  
8.4 Regulatory and Ethical Considerations 
8.4.1 Data and Safety Monitoring Plan 
After each DING intervention is attempted, the Principal Investigator will review 
medical record and video recordings and debrief the clinical staff to ascertain 
potential safety and feasibility concerns.  The Principal Investigator will provide 
oversight for emerging safety information.   
In addition, a Data Safety Monitoring Board (DSMB), comprising two clinical content 
experts and a neonatal clinical trialist, will review specified safety events 
incrementally after allocation of every 5 subjects to ensure the study does not 
impose undue extra risk on infants with CDH.  
 
8.4.2 Risk Assessment 
This trial poses a minor increase above minimal risk for this population.  While the 
trial intervention includes an invasive procedure (endotracheal intubation), this is 
standard of care for all infants with CDH.  The intervention in this trial relates to the 
timing of actions standardly performed in infants with CDH after delivery, from the 
standard (clamp the umbilical cord, intubation, and gentle ventilation) to novel 
treatment (intubation, gentle ventilation, clamp the umbilical cord).  
Risks from the study intervention: 
1. Positioning the infant on the Lifestart trolley for intubation could put tension on 
the umbilical cord, leading to cord avulsion and bleeding.  To minimize this risk, 
we have performed multi-disciplinary simulations in both the labor rooms and the 
obstetrical operating room to define the provider’s roles and identify provider 
positions around the Lifestart trolley (Figure 2).  In addition, the umbilical cord 
will be clamped immediately if the neonatologist or obstetrician has any 
concerns about the patient’s safety or the team’s ability to perform clinical 
interventions. 
2. There is the potential for the infant to become cold from exposure during the 
procedure.  We will use a warmer mattress on the LifeStart trolley to minimize 
this risk.  In addition, the intervention will last 3 minutes maximum, reducing the 
potential opportunity for cold stress.  Once the infant is moved to the infant 
stabilization suite, we will monitor his/her temperature and apply ambient heat 
for thermoregulation. 
3. For mothers delivering via Cesarean section, there is the potential for 
contamination of the surgical field from the neonatal equipment.  To minimize 
this risk, we will drape the Lifestart trolley in surgical covers and drapes, we will 
use sterile equipment when possible (such as suction catheters), and all 

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neonatal providers who will be in close proximity to the surgical field for the 
study intervention will be in sterile surgical attire. 
4. Witnessing the neonatologist intubate the infant in close proximity may cause 
emotional distress for the parents.  We will discuss their preferences before birth 
and offer the use of privacy screens if they do not want the intubation to be 
visible. 
Risks From Delayed Cord Clamping (DCC): 
DCC after birth is now widely recommended as standard care by multiple 
professional bodies (Table 1).  The safety of this practice for full term newborns and 
their mothers is well established.5 The definition of DCC varies significantly across 
published trials, ranging from 1-5 minutes after birth. 
 Infant Risks: DCC is associated with an increased risk of hyperbilirubinemia 
requiring phototherapy.  All infants in the DING trial will be monitored for 
hyperbilirubinemia and treated with phototherapy, according to the American 
Academy of Pediatrics recommendations.  DCC is not associated with increased 
risk for other studied infant morbidities. 
 Maternal Risk: DCC is not associated with increased risk of severe post-partum 
hemorrhage, any post-partum hemorrhage, or other any of the other maternal 
morbidities that have been studied.5  
Risks from Maternal Questionnaire/Interview 
Witnessing a neonatologist intubate their baby at close proximity may cause 
mothers emotional distress. Asking mothers about this potentially distressing 
experience may put them at risk of further distress.  We may uncover evidence of 
this distress or of other mental health disorders as a result of this study. Dr. Joanna 
Cole is a clinical psychologist and manager of psychosocial services in the Special 
Delivery Unit.  Dr. Cole is a member of the DING study team and will be available to 
arrange for any necessary follow-up in the event of significant parental stress or the 
uncovering of such disorders. 
The main risk from audio-recording of the interviews is breach of confidentiality. 
This risk is minimal and investigators will take steps to minimize breach of 
confidentiality (see related section).  Some people may feel uncomfortable 
having the interview recorded. Participants may skip any question or stop the 
interview at any time. 
Risks from Data collection for Historical Controls 
There could be a risk of privacy, however only coded data will be collected. All 
measures will be taken to minimize this risk. 
 

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8.4.3 Potential Benefits of Trial Participation 
Potential direct benefits include the potential physiologic benefit from the DING 
intervention.  Indirect benefits include contribution of knowledge for future infants 
with CDH. There are no potential benefits to infants in the historical controls. 
 
8.4.4 Risk-Benefit Assessment 
Given the potential direct benefit to subjects, the indirect benefit to future patients, 
and the minor increase in risk above baseline, it is reasonable to proceed with the 
study.  
8.5 Recruitment Strategy 
Parents will be recruited on an antenatal basis, either in the CFDT outpatient setting 
or in the SDU inpatient setting.  We will identify women carrying a fetus with a 
prenatal diagnoses with CDH who are at ≥32 weeks gestation.  If the potential 
subject is eligible for co-enrollment in additional studies designed with antenatal 
consent process, we will coordinate with those study teams to ensure a cohesive 
approach to the parents.    
 CFDT: We will work with the CFDT staff to identify potentially eligible women on 
the outpatient schedule. These women meet with a neonatologist for a consult 
during their scheduled antepartum visits between 33-35 weeks gestation. After 
gaining permission from the neonatologist who performed the consult, a member 
of the research team will approach the potential subject’s parents in person.  
 SDU inpatient: If a potential subject’s parents were not approached in the CFDT 
setting or did not make a decision in the CFDT setting, a member of the study 
team will offer study participation in the inpatient SDU setting.  All admissions to 
the SDU are sent out to the NICU clinical team in real time via ASCOM system 
message.  The study team will coordinate with the clinical team to be alerted 
when women carrying a fetus with CDH are admitted to the SDU.  A study team 
member will offer study participation to the parents at that time, as long as the 
mother is not in the active phase of labor.  
In both environments, the study team will leave written information for the subject’s 
guardian to review before obtaining informed consent.  No direct advertising 
directed at potential participants will be used. However, we will be including brief 
information on the DING trial on the CFDT website. 
 
Approximately 40-50 infants with CDH are referred to the CFDT and born in the 
SDU per year, ensuring the recruitment goal is feasible. 
8.6 Informed Consent/Assent and HIPAA Authorization 
A member of the study team (investigators or coordinator) will obtain informed 
consent and HIPAA Authorization using a combined consent-authorization 
document.  As the study subjects are newborns, assent will not be obtained.  

DING Protocol 
PI: Foglia 
 
 
 
 
 
 
 
21
 CFDT: The study team member will approach the potential parents in a 
private consultation room in the outpatient CFDT office suite. The study team 
member will describe the study and review the informed consent document.  
The team member will review all risks and benefits of study participation, will 
confirm that the parents understand the nature of the study, and will answer 
all study related questions. 
 SDU: The study team member will approach the potential parents in a private 
inpatient room in the SDU. The study team member will describe the study 
and review the informed consent document.  The team member will review 
all risks and benefits of study participation, will confirm that the parents 
understand the nature of the study, and will answer all study related 
questions. 
No member of the study team will pressure the parent or guardian to enroll the 
subject. There is no limit on the time allotted to make the decision, with the caveat 
that potential subjects may no longer be eligible if parents have not made a decision 
prior to delivery. 
Prior to the start of any study-related procedure, a signed and dated informed 
consent and HIPAA authorization must be obtained and documented in the study 
binder. Once it has been determined that the infant meets all inclusion criteria and 
no exclusion criteria, the infant will be considered allocatable.   
 
A waiver of consent/parental permission, assent, and HIPAA authorization is 
requested for control subjects from study #3779 as they have already provided 
consent for future research. 
 
8.6.1 Waiver of Assent 
We request a waiver of assent, as all subjects are newborns who do not have 
the capability to provide assent. 
8.7 Payment to Subjects/Families 
Subjects and their families will not receive any payment for study participation.   
8.7.1 Gifts 
No gifts or tokens of appreciation will be given to subjects or families. 
9 
PUBLICATION 
Once all 40 subjects (20 in the interventional arm and 20 in the historical controls) 
have been evaluated and the data analysis is complete, the aggregate results will 
be prepared and submitted for publication in a peer-reviewed journal.  No 
identifiable data will be included in the manuscript for publication. 

DING Protocol 
PI: Foglia 
 
 
 
 
 
 
 
22
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