Pilot Randomized Control Trial of Necrotizing Enterocolitis Screening Abdominal Radiograph Versus Bowel Ultrasound Plus Abdominal Radiograph in Premature Neonates
Phase: NA
Conditions: Enterocolitis, Necrotizing, Premature Infant
Sponsor: Children's Mercy Hospital Kansas City

SHORT TITLE:NEC and Premies 
 
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PROTOCOL TITLE: 
Pilot Randomized Control Trial of Necrotizing Enterocolitis Screening Abdominal 
Radiograph versus Bowel Ultrasound plus Abdominal Radiograph in Premature Neonates  
 
PRINCIPAL INVESTIGATOR: 
Erin Opfer, DO 
Children’s Mercy Hospital and Clinics 
Assistant Professor 
Department of Radiology 
816-324-3273 
ekopfer@cmh.edu 
 
 
 
VERSION NUMBER/DATE: 
Version 4.0 
February 26, 2019 
 
REVISION HISTORY 
 
This Revision History table is provided for the benefit of study team version 
control.  If this table will not be useful to your team, you do not need to include it. 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives ................................................................................................................ 5 
3.0 
Background .............................................................................................................. 5 
4.0 
Study Endpoints ....................................................................................................... 5 
5.0 
Study Intervention/Investigational Agent ................................................................ 7 
6.0 
Procedures Involved................................................................................................. 7 
7.0 
Data and Specimen Banking .................................................................................... 9 
8.0 
Genetic Analysis Information .................................................................................. 9 
9.0 
Sharing of Results with Subjects ........................................................................... 11 
10.0 Study Timelines ..................................................................................................... 11 
11.0 Inclusion and Exclusion Criteria ............................................................................ 12 
12.0 Vulnerable Populations .......................................................................................... 12 
13.0 Local Number of Subjects ..................................................................................... 12 
14.0 Screening and Recruitment Methods ..................................................................... 12 
15.0 Reimbursement, Payment and Tangible Property provided to subjects ................ 13 
16.0 Withdrawal of Subjects .......................................................................................... 13 
17.0 Risks to Subjects .................................................................................................... 13 
18.0 Potential Benefits to Subjects ................................................................................ 13 
19.0 Investigator Assessment of Risk/Benefits Ratio. ................................................... 14 
20.0 Data Management and Confidentiality .................................................................. 14 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects .......................... 14 
22.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 15 
23.0 Compensation for Research-Related Injury ........................................................... 15 
24.0 Economic Burden to Subjects ................................................................................ 15 
25.0 Permission/Assent/Consent Process ...................................................................... 16 
26.0 Process to Document Permission/Assent/Consent................................................. 17 
27.0 Setting .................................................................................................................... 17 
28.0 Resources Available............................................................................................... 17 
29.0 Multi-Site Research ............................................................................................... 18 
30.0 International Research ........................................................................................... 18 
 
 
 

SHORT TITLE:NEC and Premies 
 
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1.0 
Study Summary 
 
Study Title 
Pilot Randomized Control Trial of Necrotizing Enterocolitis 
Screening using Abdominal Radiograph versus Bowel 
Ultrasound plus Abdominal Radiograph in Premature 
Neonates 
 
 
Study Design 
Pilot Randomized Controlled Trial 
Primary Objective 
To establish the feasibility and pilot the design and delivery 
of a diagnostic randomized controlled trial (RCT) of BUS for 
NEC evaluation.  
Secondary 
Objective(s) 
• Explore whether the addition of BUS to the NEC 
diagnostic and monitoring pathway will change: 
1. The rates of medical versus surgical 
management  
2. The days between NEC diagnosis and 
surgical intervention for those that need it  
3. The days NPO for those that get medical 
management 
• Develop a predictive model for NEC diagnosis  
• Develop a predictive model for medical versus 
surgical management 
• Explore the usefulness of serial fecal calprotectin 
levels as a predictive biomarker for NEC  
 
 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
N/A 
IND/IDE #  
n/a 
Study Population 
Premature NICU babies under 32 weeks gestational age 
Sample Size 
160 subjects enrolled 
Study Duration for 
Individual 
Participants 
From enrollment until discharge or transfer from CMH 
Study Specific 
Abbreviations/ 
Definitions  
NEC – Necrotizing Enterocolitis 
BUS – bowel ultrasound 
AXR – abdominal radiographs 
FC – fecal calprotectin 
NICU – Neonatal Intensive Care Unit 
CMH – Children’s Mercy Hospital 
MRN – medical record number 
OSH – outside hospital 
LAR – legally authorized representative 
P/A/C – permission/assent/consent 

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RCT – randomized controlled trial 
NPO – nothing by mouth 
VLBW – very low birth weight 
 
 

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2.0 
Objectives 
2.1     The overall primary objective is to establish the feasibility and pilot the design 
and delivery of a diagnostic randomized controlled trial (RCT) of BUS (bowel 
ultrasound) for NEC evaluation which will lead to a successful application for a 
larger, multi-center clinical trial in the future. This program of research is 
anticipated to have a significant positive impact in the timely and accurate diagnosis 
of NEC in preterm infants.  
We plan to accomplish our overall objective for this project by pursuing the 
following specific aims: 
1. Explore whether the addition of BUS to the NEC diagnostic and 
monitoring pathway will change: 
(a) The rates of medical versus surgical management  
(b) The days between NEC diagnosis and surgical intervention for those 
that need it  
(c) The days NPO for those that get medical management 
2. Develop a predictive model for NEC diagnosis  
3. Develop a predictive model for medical versus surgical management  
2.2 
A secondary exploratory objective is to determine the usefulness of serial 
fecal calprotectin levels as a predictive biomarker of NEC. We hypothesize that 
tracking changes in fecal calprotectin levels from baseline can identify preterm 
infants with and without NEC. 
3.0 
Background 
Necrotizing enterocolitis (NEC) is the most common bowel disease in premature 
and low birth weight neonates. NEC is defined by the loss of mucosal integrity of 
the bowel wall enabling bacteria and other toxins to permeate into the bowel 
causing ischemia and necrosis which can lead to bowel perforation and sepsis (1, 
2).  NEC can result in substantial morbidity and mortality and prolonged hospital 
stay.  
 
In the past, abdominal radiography has been scored on a standard scale that 
correlated with outcomes. Duke University Medical Center developed a 
standardized ten-point radiographic scale, the Duke Abdominal Assessment Scale 
(DAAS) (Appendix B) and was proven to be directly proportional to the severity 
of NEC on patients that underwent surgery (3, 4). Abdominal radiographs are 
assessed for gas pattern, bowel distention, location and features, pneumatosis (gas 
in bowel wall), portal venous gas, and pneumoperitoneum (free air in peritoneal 
cavity) to indicate the level of suspicion of NEC (3, 4).  The use of abdominal 
radiographs is the most common assessment for suspected NEC in infants, 
however, there have been recent studies done on the utility of bowel ultrasound to 
aid in early diagnosis of NEC due to the ability to evaluate peristalsis, 
echogenicity and thickness of bowel wall, pneumatosis and the capability of doing 
color Doppler to evaluate blood perfusion(2). A University of Toronto study used 
ultrasound to assess bowel perfusion with color Doppler in neonates and found a 
correlation between absence of bowel wall perfusion and the increased severity of 
NEC on surgical pathology (5).  Although there are similar signs found between 
abdominal radiography and bowel ultrasound, some of the more severe features 

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such as, pneumoperitoneum, were found to be more sensitive on bowel 
ultrasound, thus potentially leading to more definitive treatment (5).  Currently, 
there is no good study evaluating whether the use of bowel ultrasound affects 
clinical outcomes in VLBW patients over the use of abdominal radiography alone. 
 
The use bowel ultrasound has yet to be adopted in the setting of suspicion for 
NEC at our institution. This is primarily due to the lack of expertise of the 
ultrasound technologists, radiologists and clinicians. With literature dating back to 
2005(5, 6) supporting the use of bowel ultrasound in diagnosis of severity of 
NEC, we would like to see if a regimen involving combined ultrasound and 
radiograph screening for NEC would make a difference in clinical outcomes 
(morbidity, mortality, and length of stay (LOS)) compared with radiograph 
screening alone.  
 
 
Calprotectin is a protein found in the stool that, at elevated levels, indicates 
gastrointestinal inflammation. The addition of fecal biomarkers to the diagnostic 
work up for NEC also has promising impact. It has been suggested that fecal 
calprotectin levels obtained at the time of suspicion of NEC may be a useful 
noninvasive indicator to determine the severity of inflammation in the intestine and 
whether it is related to NEC or other forms of inflammation. (8) Correlation of the 
fecal biomarkers with findings on BUS may be helpful to more definitively 
diagnose NEC. 
 
 
4.0 
Study Endpoints 
4.1 
The primary endpoint for this study will be feasibility of 
recruitment into a diagnostic RCT and implementation of BUS 
intervention in infants with suspected NEC. Feasibility parameters to be 
assessed include recruitment, randomization, retention, and crossover. 
Recruitment will be measured as proportion of eligible infants who are 
enrolled, while randomization will be proportion of enrolled infants who 
develop NEC suspicion and undergo randomization. Retention will be 
defined as proportion of infants who complete the study. Crossover will be 
measured by proportion of infants randomized to standard of care who 
crossover to BUS arm. Successful implementation of intervention will be 
assessed by (1) proportion of properly completed BUS studies by 
sonographers; (2) proportion of adherence to standardized reporting 
template by radiologists, and (3) timeliness of stool collection in proximity 
to the BUS. For the secondary endpoint measures, time to achieve full 
enteral feeds will be defined as days to reach enteral feeds of 
120mL/kg/day following suspension of feeds due to suspected NEC; and 
total antimicrobial days will be defined as days treated with empiric 
antibiotics due to suspected NEC. For the exploratory aim, the primary 
endpoint will be changes in serial fecal calprotectin levels and its 
association with NEC diagnosis.  

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5.0 
Study Intervention/Investigational Agent 
5.1 
Patients who consent for this study will undergo a series of BUS 
and noninvasive fecal calprotectin tests over the course of their 
enrollment. There are no known adverse effects of BUS. 
 
6.0 
Procedures Involved 
6.1 Experienced research coordinators will screen for potentially eligible infants 
daily. NICU staff may notify someone from the study team about potential subjects. 
Infants successfully enrolled in the study will be clearly identified by signage at the 
bedside and updated lists in the work room. All enrolled subjects will have a 
baseline fecal calprotectin level obtained at the time of enrollment or with next 
stool. If an enrolled infant develops concern for NEC (as determined clinically by 
treating neonatologist), a sealed envelope will be opened to reveal to which arm the 
infant is randomized: (A) AXR only (standard of care) or (B) AXR and BUS 
(intervention).  
Intervention. Infants randomized to the AXR only arm will obtain an AXR as per 
standard of care (see Figure). Repeat AXR, if any, will be left to the discretion of 
the treating neonatologist. In this arm, no BUS study will be performed unless the 
attending neonatologist decides it is clinically indicated. This situation is expected 
to be exceedingly rare, as BUS is not part of the standard of care for NEC 
evaluation. Infants randomized to the AXR and BUS arm will also get an AXR, 
with repeat AXR left to the discretion of the treating neonatologist. In addition to 
this standard of care, infants randomized to this arm will receive a BUS as the 
intervention. This BUS will be ordered at the same time as the initial AXR and will 
be performed within six hours of the order being placed. Since CMH has overnight 
and weekend sonographers, BUS can be done performed 24/7. An additional BUS 
and fecal calprotectin level will be performed once every 24-hours until clinical 
suspicion is no longer warranted. Enrolled patients who may undergo multiple 
“suspected NEC” encounters during the course of their admission will remain in 
the same arm throughout the study.  
 
 
 
 
 
 
 
 
 
 
 
Enrolled 
infant with 
concern for 
NEC
Randomized 
to AXR only
NEC concern 
resolved
No further 
imaging
Still concern 
for NEC
Repeat AXR 
per provider
Randomized 
to AXR + 
BUS
NEC concern 
resolved
No further 
imaging
Still concern 
for NEC
Repeat AXR 
per provider
Repeat BUS 
dailyx3

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Management. All AXR and BUS exams will be interpreted by board-certified 
pediatric radiologists, and all imaging results will be available for clinicians to 
review as part of the subject’s medical record. Fecal calprotectin levels will be 
documented in the patient’s research data, but not included in the subject’s medical 
record. All laboratory tests and treatment, including antibiotics or bowel rest, will 
be left to the discretion of the treating neonatologist. Participation in the study will 
end at the time of discharge or transfer.  
BUS performance and interpretation. US performance and interpretation will be 
performed by a sonographer and radiologist, respectively, as per standard clinical 
work-flow. All BUS results will be available to the study team (i.e. no blinding). 
Variability in performance of US by sonographers will be minimized by pre-study 
training and quick reference cards in each US machine as detailed above. Likewise, 
variability in US interpretation will be minimized by the pre-study training as well 
as the use of a standardized template for reporting US results (see Appendix). All 
study US exams will be over-read by the study radiologists to ensure accurate 
interpretation. In cases of differences in their readings, final interpretation will be 
made by the study radiologists and these results will be communicated to the 
clinical team.  
Fecal calprotectin measurement. Stool will be collected from a diaper following 
study enrollment regardless of rate of feeds.  We will do an additional collection of 
stool after five weeks of life to get a baseline calprotectin level.  “Baseline” is 
defined as an infant who is greater than or equal to five weeks of age and is 
tolerating full enteral feeds of at least 120 mL/kg/day. All stool samples will be 
collected by the NICU nurse or study staff.  Stools can be stored for up to 72 hours 
if needed and then processed using the Fecal Calprotection High Range 
Quantitative Quantum Blue assay. All results will be recorded in Redcap.  If a baby 
develops a concern for NEC, the next three stool samples at least a day apart will 
be collected for FC analyzation.  An additional stool sample will also be collected 
at the resolution of NEC watch, which is defined by tolerance of ≥ 120mL/kg/day 
of enteral feeds for at least two days.  Infants who have repeated concern for NEC 
will again have the first three stool samples collected with each event, with another 
stool also collected at resolution of NEC.  The stool samples will be kept suspended 
in a buffer in a test tube for the duration of the study in the event a sample needs to 
be retested.  
6.2 Protected health information (PHI) to be collected for the purpose of this study 
alone will include: DOB, gender, race, MRN, account number, dates of abdominal 
radiographs, ultrasound examinations, lab and vital signs. All data will be collected 
and kept in a password protected database (REDcap) that only CMH study 
personnel will have access to. A master linking list between MRN and study-ID 
numbers will be kept separately in REDcap and will be destroyed upon completion 
of the study. The research record generated will consist of an excel spreadsheet 
from the data dictionary within REDcap. Security measures include: storage of the 
Figure: Flow diagram of study following randomization.  

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data on a password protected computer in a restricted access departmental folder 
limited to only study personnel. 
7.0 
Data and Specimen Banking 
7.1 
By consenting to the study, patients will allow the collected stool samples 
to be stored for future research in Dr. Venkatesh Sampath’s laboratory (IBC 
protocol 18-28).  
7.2 
The Premature Infant Stool Microbiome Repository will be comprised of 
stool samples that will prospectively be used to study NEC and/or the microbiome 
of the bowels in premature infants.  The purpose of this database is to provide a 
CMH-wide bank of specimens that will be used for future research for projects 
involving the study of NEC and/or bowels of premature infants. 
7.3 
Repository Director – The Director is responsible for the design, 
development, implementation, and management of the repository. The Director is 
the person ultimately responsible for repository’s compliance with all applicable 
federal, state, local laws and CMH institutional policies. The Director is 
responsible for ensuring: 1) the Repository operates within budget; 2) Informed 
consent is obtained, documented, and stored in compliance with IRB regulations 
and institutional policies; 3) Repository personnel are appointed, trained, and 
supervised by the Director to ensure there is an adequate number of staff with 
adequate experience and assigned responsibilities commensurate with 
capabilities; and 4) employ a quality assurance system to ensure the Repository’s 
operation is in compliance with the SOP, IRB approval, regulations, and 
institutional policies. 
7.3.1 Repository Manager – The Repository Manager maintains the 
operation of the day-to-day activities of the Repository, such as submitting 
accurate and timely information for continuing review, reporting to the IRB any 
adverse events, unexpected problems, or protocol deviations/violations, and 
maintaining repository records appropriately. 
7.3.2 Technical staff – Responsible for implementation of policies and 
procedures established by Director. Duties of each staff member are 
commensurate with their job description. 
7.3.4 Contributing Investigators – Persons who provide data/specimens 
to the repository for storage. 
7.3.5 Recipient Investigators – Persons who query or extract 
data/specimens from the repository for use in future research projects. 
Sample size is approximately 80 donors per year from CMH in accordance with 
inclusion/exclusion criteria to the NEC and Preemies study. (Section 11.0).  Stool 
will be collected by the bedside ICN RN directly from the diaper into a specimen 
cup.  A small amount of stool will be taken in order to complete the calprotectin 
testing, the unused stool will be stored in the repository.  
Time-Line: Stool samples should be stored at 4 degrees C. For microbiome 
analysis, stools should be transferred to Eppendorf tubes and stored at -80 degrees 
C preferably within 24-36 h. 

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Procedure: 
* Wash your hands thoroughly before beginning the collection. 
* Collect pre-weighed Eppendorf tubes from Sampath Lab (note weight). 
* Open the Eppendorf tubes. 
* Using the wooden stick, collect a small amount of feces from the specimen cup. 
* Weigh the tube with feces. 
* Discard the rest of the feces after completing Calprotectin studies in the usual 
way. 
* Firmly screw the lid on the specimen container (taking care that it is not cross-
threaded). 
* Please ensure the specimen jar is correctly labelled with your de-identified study 
code number and samples number (ex., ID-Stool 1, Stool 2), date & time sample 
was collected. Please record the weight of stool in the tubes. 
* Place the sealed specimen jar in the plastic hazard bag provided and 
immediately store -80 0C. 
INFANT STOOL SAMPLE LABEL 
Participant ID #: -------------------------------- 
Date of collection: ___/___/___ 
Stool sample id:  
Day of life stool was collected: 
Time Collected: ___:___ am/pm 
Weight of stool:---------------------- 
7.3 
The stool samples will be labeled with the study ID of the enrolled patient 
in the NEC and Preemies study.  The stool samples will be labeled with a letter in 
alphabetical order for subsequent stool samples (i.e. 1-a, 1-b, etc.).  
7.4 
Repository Personnel will view and record PHI for inclusion into the 
Repository: [Manager, Staff, etc.]. Medical information is protected under federal, 
state, local privacy laws and under the terms of the consent process. CMH 
employees with access to the repository may not disclose information in 

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accordance with the Administrative Policy, Confidentiality. Database is password 
protected and accessible only by Repository personnel. 
7.5 
Only projects researching NEC or bowel microbiome in premature infants 
will be considered for use of the Premature Infant Stool Sepository. The recipient 
investigator must have a protocol approved by an IRB for this purpose or an 
approved Exemption from the IRB. This documentation must be provided before 
samples/data are distributed. 
Recipient investigators include CMH investigators and non-CMH investigators. 
7.6  
A written 1-2 page request summarizing the project for which the samples 
are requested must be submitted to the Repository Director. The request must 
contain the following details: number of samples, ethnicity of donors, amount and 
concentration of DNA in addition to a brief project summary (abstract), the 
specific aims/goals, significance and experimental design and methods (Appendix 
5). 
 
Only recipient investigators authorized by the Repository Director will have direct 
access to the Repository.  The Repository will not release any direct identifiers to 
any recipient investigators (see Form X: Recipient investigator query form). 
 
Information accessed by non-CMH employees may also be bound under non-
disclosure or confidentiality agreements.  Confidentiality Disclosure Agreement 
(CDA) will be signed and kept on file for persons not bound by CMH 
Administrative Policy, Confidentiality in order to protect the sensitive information 
that they have access to.  See Administrative Policy, Confidentiality Agreement. 
 
Sample:  
Data 
Repository 
Personnel 
CMH 
Recipient 
Investigators  
Non-CMH 
Recipient 
Investigators 
Identifiable 
data set 
(Form A) 
All/Manager 
only 
Available 
upon request 
and IRB 
approval 
Not released 
De-
identifiable 
data set 
(Form B) 
All 
Available 
upon request 
and IRB 
approval 
Available 
upon request 
and IRB 
approval 
 
8.0 
Genetic Analysis Information 
8.1 N/A 
9.0 
Sharing of Results with Subjects 
9.1    N/A 
10.0 Study Timelines 

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10.1     The duration of participation of patients that enroll in the study 
will be from time of enrollment to discharge or transfer from CMH 
10.2      The study timeline is as follows:  
Stage 1, patient accrual - 10/1/2018 – 12/31/2020 
Stage 2, data analysis - 1/1/2021 - 3/31/2021 
Stage 3, grant applications- 3/1/2021 
Projected start date is upon IRB approval. Projected start date 10/1/2018 
Total length of time: 3 years 
 
 
11.0 Inclusion and Exclusion Criteria 
Inclusion Criteria 
• Neonates born prior to or at 32 weeks gestation admitted to NICU at CMH 
Exclusion Criteria 
 
• Infants with chromosomal or multiple congenital anomalies  
• Unable to ultrasound the bowel (e.g. gut in silo, omphalocele, gastroschisis) 
• Infants who are greater than 36 corrected weeks upon admission 
• Infants who have had recent abdominal surgery 
• Infants who have had a previous bowel perforation 
 
 
12.0 Vulnerable Populations 
12.1 This study involves no greater than minimal risk to the subjects enrolled. 
BUS is a noninvasive imaging tool used in standard of care procedures often for 
premature infants in the NICU currently.  Fecal calprotectin sampling is also 
noninvasive and would only involve a stool sample obtained from a diaper.  
Consent will be obtained from the patients LAR after a full explanation of the 
study is given and any questions the LAR has are answered. Assent will not be 
obtained due to age. 
 
13.0 Local Number of Subjects 
13.1 This pilot study will enroll 80 NICU patients per year, aiming to 
randomize 40 patients a year with suspected NEC.   
 
14.0 Screening and Recruitment Methods 
14.1 Potential subjects will be screened and recruited in the NICU at 
Children’s Mercy Hospital upon admit.  Screening will be done by a 

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CMH NICU fellow or research coordinator on the study and consent 
will be obtained shortly after eligibility is confirmed. 
14.2 The source of subjects will solely come from the CMH NICU. 
14.3 Potential subjects will be identified by the NICU staff and a member 
of the study team will be notified to confirm eligibility and approach 
the subject and LAR to obtain consent if desired. 
14.4 A pre-screening log will be maintained for the purpose of tracking 
enrollment.  This will include DOB, MRN, eligibility, and choice to 
participate. This will ensure a patient is not approached more than 
once. 
15.0 Reimbursement, Payment and Tangible Property provided to 
subjects 
15.1   N/A 
 
16.0 Withdrawal of Subjects 
16.1 A subject may be withdrawn without their consent if they undergo 
any medical procedure during the course of their admission that 
excludes them from safely undergoing a BUS. 
16.2 Subjects may choose to discontinue study participation at any time, 
for any reason, specified or unspecified, and without prejudice. 
Subjects may be discontinued from the study for any of the 
following reasons: 
• At the subject’s or their parent’s/LAR’s request 
• At the discretion of the site investigator as deemed 
appropriate for any reason 
Procedures for orderly termination will include a discussion with the 
parents or LAR for the reasons behind early termination.  
16.3 If a subject withdraws from the research study, data that has already 
been collected may still be used; however, no new information will 
be collected except information related to adverse events or other 
safety issues. 
17.0 Risks to Subjects 
17.1 This study involves no greater than minimal risk to the subjects 
enrolled. BUS is a noninvasive imaging tool used in standard of care 
procedures often for premature infants in the NICU currently.  Fecal 
calprotectin sampling is also noninvasive and would only involve a 
stool sample obtained from a diaper.   
 
18.0 Potential Benefits to Subjects 

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18.1 There may be no direct benefit to the patient in the study, however, 
imaging done as part of the study will be available to any treating 
physician and may be helpful in medical management of the patient.  
Any procedures or treatments performed as a result from the imaging 
will be the financial responsibility of the patient.  
19.0 Investigator Assessment of Risk/Benefits Ratio: (IRB makes the 
final determination)  
 
Select as applicable: 
Pediatric Risk Category: 
X 
Category 1  Research not involving greater than minimal risk  
(45 CFR §46.404 and 21 CFR §50.51)   
 
Category 2 
Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the 
individual 
subjects. (45 CFR §46.405 and 21 CFR §50.52) 
 
Category 3 
Research involving greater than minimal risk and no 
prospect of direct benefit to individual subjects, but 
likely to yield generalizable knowledge about the 
subject's disorder or condition.  
(45 CFR §46.406 and 21 CFR §50.53) 
 
Category 4 
Research not otherwise approvable which presents 
an opportunity to understand, prevent, or alleviate a 
serious problem affecting the health or welfare of 
children. (45 CFR §46.407 and 21 CFR §50.54) 
Select if applicable: 
Adult Risk Category: 
 
Not Greater than Minimal Risk 
 
Greater than Minimal Risk 
 
20.0 Data Management and Confidentiality 
20.1 
This is a pilot study only to evaluate feasibility of a larger clinical trial.  
We will use the pilot data in the future to perform a power analysis for the larger 
study. 
20.2 
We anticipate having to approach ~100 patients/year to achieve the 40 
patients/year needed for our pilot study.  We are assuming a NEC suspicion 
incidence rate of 50% and approximately 20% of parents/patients declining to 
consent for the study (e.g. 100 patients * 80% consent rate * 50% with NEC 
suspicion = 40 patients/year). 
20.3 With a target of 80 patients randomized, we anticipate the enrollment 
period to last ~2 years. We will stop consenting patients as soon as we meet our 
desired enrollment. 
20.4 
A certificate of confidentiality will not be sought for this study. 
20.5 
Study data will be evaluated by the PI throughout the duration of 
the study for QA. 
20.6 
Patient information will be maintained in a REDCap application 
and will be housed within the CMH Data Center by the Division of 
Biomedical Informatics.  The hosting server has an internal failover two-
node cluster.  The CMH Data Center is constantly staffed by qualified 
personnel and physical access is limited to authorized personnel.  The 

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Center has optimized conditions for the servers and stabilized electrical 
supply.  The database has a full backup.  The database server is located 
inside the CMH corporate firewall.  A person must have CMH system 
access to loin.  Additional security for the study patient database restricts 
access to only those persons specifically granted authorization by the 
Principle Investigator. It is possible for data to be downloaded from 
REDCap.  Individuals who lack authority to see confidential data can 
download reports with non‐identifiable data only. The core research group 
will have the ability to download sensitive fields and if such a download 
occurs, REDCap maintains a record of who, what, when, and to where 
copies of the database were imported.   
 
21.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
N/A 
22.0 Provisions to Protect the Privacy Interests of Subjects 
22.1 Privacy interests for subjects will be maintained by limiting 
interaction with subjects and LAR to only study personnel at the 
discretion of the treating physician. 
22.2 This study is voluntary, the physicians involved do not have any 
financial gain or interest with the study. Subjects may withdraw 
participation at any time and their care and treatment at CMH will 
not be compromised. Subjects and their families will be told that 
there participation is voluntary and that they may stop at any time. 
22.3 Only IRB approved members of the study team will be granted 
access to the study folder located on the network drive or the 
REDCap database.  Additionally, study team members who are 
responsible for collected data only will be granted limited access to 
REDCap, allowing them to record data only.  
22.4 PHI to be accessed and/or recorded for this research study includes: 
DOB, MRN, dates of service (BUS exams, FC results, HSCT, lab 
dates and dates of severity milestones and death if applicable) will be 
recorded. 
22.5 HIPAA authorization will be wrapped into 
permission/assent/consent form. 
23.0 Compensation for Research-Related Injury 
23.1 There is no more than minimal risk to subjects. 
24.0 Economic Burden to Subjects 
24.1 There will be no cost to patients for participating in this study.  All 
BUS imaging and Fecal Calprotectin tests will be the covered by 
study funds.  However, patients will be charged for any standard of 

SHORT TITLE:NEC and Premies 
 
Page 16 of 18 
Version 1.4 dated 7.13.18 
care imaging, procedures, or treatments that coincide with their 
diagnosis (i.e. AXR, antibiotics, surgery).   
25.0 Permission/Assent/Consent Process 
25.1 Permission/Assent/Consent will be obtained by a LAR from all 
patients wishing to participate. 
• 
The p/a/c process will take place in the CMH NICU at the 
patient’s bedside. 
• 
The patient’s LAR will be given time to review materials and 
ask any questions. 
• 
We will be following CMH research policies on informed 
consent.   
• 
We will have the option to obtain consent via telephone in the 
event a parent or guardian is unavailable at the bedside or only 
comes on weekends.  
• 
We will follow CMH policy 10.05 Telephone and 
Telemedicine Consent Process.  
• 
Parental permission will be obtained from one parent or LAR. 
• 
This study will only occur in Missouri at the Children’s Mercy 
Hospital – Adele Hall.  
• 
Other than biological parents, LARs such as an adoptive parent 
will be allowed to consent for a child’s participation in this 
study.   
Consent at 18 years of age, when minor subjects become adults 
N/A 
Waiver or Alteration of Parental Permission or Child Assent 
Process (permission and/or assent will not be obtained, required 
information will not be disclosed, or the research involves 
deception) 
N/A 
Waiver or Alteration of Consent Process (consent will not be 
obtained, required information will not be disclosed, or the 
research involves deception) 
N/A 
Non-English Speaking Subjects 
• 
P/A/C forms will be translated into Spanish by ORI 
Translations program. 

SHORT TITLE:NEC and Premies 
 
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Version 1.4 dated 7.13.18 
Cognitively Impaired Adults 
N/A 
Adults Unable to Consent  
N/A 
26.0 Process to Document Permission/Assent/Consent 
26.1 Study staff will be following CM Research Policy 10.04 Obtaining 
Permission/Assent/Consent.  
26.2 We request a waiver of documentation of P/A/C for patients in 
which phone consent was obtained since the study involves no more 
than minimal harm. 
 
27.0 Setting 
27.1 Potential subjects will be recruited from the NICU at CMH Adele 
Hall.  NICU staff may notify study team members of an eligible 
patient and eligibility will be confirmed upon screening.  Once 
eligibility is confirmed, the subject will be approached for consent.  
All procedures (BUS, AXR, and fecal calprotectin testing) will take 
place at the patient’s bedside in the CMH NICU. 
28.0 Resources Available 
28.1 
The facilities and other resources available to the research team include 
everything needed to undertake and complete the proposed pilot study 
successfully. The NICU at CMH provides clinical care to over 150 preterm 
infants ≤ 28 weeks gestation per year and thus provide access to sufficient 
patients. The culture of clinical research is vibrant in the NICU with high 
recruitment rates for current studies. US services at CMH are also robust. CMH 
has in-house sonographers to perform US and radiologists to interpret these 
studies 24/7. Each member of the collaborative team has strong commitment from 
their departments for this study in the form of (1) protected research time, (2) cost 
sharing of salaries, (3) administrative support, and (3) research coordinator effort. 
In summary, the outstanding facilities, strong intellectual environment, and 
abundant resources available to the team are strongly supportive of the proposed 
research and overall success of the project. 
There are 20 sonographers which are all registered diagnostic medical 
sonographers (RDMS). 18 of the sonographers have also passed their 
pediatric sonography boards.  
All imaging will be performed portable in NICU by standard portable radiography 
(GE) and ultrasound equipment (GE Logiq E9 and Zonare Z-One Smartcarts) 
already in practice at our institution. 

SHORT TITLE:NEC and Premies 
 
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Version 1.4 dated 7.13.18 
Fecal calprotectin tests will be performed on Quantum Blue Reader testing devices 
that utilize Fecal Calprotectin fCAL high range tests and CAKEX Cap Devices to 
obtain calprotectin levels.  
 
Dr. Alain Cuna, one of the Co-Investigators, will present the proposed 
study at a CMH NICU Conference held monthly to ensure all NICU 
physicians are aware of the upcoming process and logistics of the study.  
 
29.0 Multi-Site Research 
29.1 N/A 
30.0 International Research 
30.1 N/A 
 
 
REFERENCES 
 
1.  
M. Epelman et al., Necrotizing enterocolitis: review of state-of-the-art 
imaging findings with pathologic correlation. Radiographics 27, 285-305 (2007). 
2.  
J. Staryszak et al., Usefulness of ultrasound examinations in the 
diagnostics of necrotizing enterocolitis. Pol J Radiol 80, 1-9 (2015). 
3.  
C. A. Coursey et al., Radiologists' agreement when using a 10-point scale 
to report abdominal radiographic findings of necrotizing enterocolitis in neonates 
and infants. AJR Am J Roentgenol 191, 190-197 (2008). 
4.  
C. A. Coursey et al., Radiographic predictors of disease severity in 
neonates and infants with necrotizing enterocolitis. AJR Am J Roentgenol 193, 
1408-1413 (2009). 
5.  
R. Faingold et al., Necrotizing enterocolitis: assessment of bowel viability 
with color doppler US. Radiology 235, 587-594 (2005). 
6.  
W. Y. Kim et al., Sonographic evaluation of neonates with early-stage 
necrotizing enterocolitis. Pediatr Radiol 35, 1056-1061 (2005). 
7.  
M. Epelman, A. Daneman, D. Podeberesky, L. Averill, K. Darge, paper 
presented at the Radiological Society of North America, Chicago,  2015 
8. Nakayuenyongsuk, W., Christofferson, M., Stevenson, D. K., Sylvester, K., Lee, 
H. C., & Park, K. (2018). Point-of-Care Fecal Calprotectin Monitoring in Preterm 
Infants at Risk for Necrotizing Enterocolitis. THE JOURNAL OF PEDIATRICS, 
100-103.